Small molecule activation of PKM2 in cancer cells induces serine auxotrophy
Open accessAbstract
Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM2 isoform, effectively constraining lower glycolysis. Here, we report the discovery of PKM2 activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM2 activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the nonessential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM2 activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM2 expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Activation of pyruvate kinase can inhibit cancer cell proliferation and tumor growth in some settings.
“Indeed, activation of pyruvate kinase can inhibit cancer cell proliferation and tumor growth in some settings (Anastasiou et al., 2012; Kung et al., 2012; Walsh et al., 2010), but because pyruvate kinase expression is dispensable for the growth of some tumors (Cortes-Cros et al., 2013; Israelsen et al., 2013), whether pyruvate kinase activation will lead to durable responses remains an area of”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Kung et al., 2012
Activating PKM2 with small-molecule agonists increases PEP-to-pyruvate conversion, reduces flux of glycolytic intermediates toward anabolic pathways, and slows tumor cell growth.
“Activating PKM2 by using small-molecule agonists increases PEP-to-pyruvate conversion, reducing the flux of glycolytic intermediates toward anabolic pathways and slowing tumor cell growth (56, 60).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [60]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197 · see citing works
Self-citationBioconductor: open software development for computational biology and bioinformatics
Gentleman, R., Carey, V., Bates, D., Bolstad, B., Dettling, M., Dudoit, S., Ellis, B., Gautier, L., Ge, Y., Gentry, J., et al. (2004) · Genome Biology · doi:10.1186/gb-2004-5-10-r80 · Cited by 13,133 · see citing works
Smyth, G. K. (2004) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1027 · Cited by 11,829 · see citing works
Exploration, normalization, and summaries of high density oligonucleotide array probe level data
Irizarry, R. A. (2003) · Biostatistics · doi:10.1093/biostatistics/4.2.249 · Cited by 10,603 · see citing works
The metabolism of tumors in the body
Warburg, O., Wind, F., & Negelein, E. (1927) · Journal of General Physiology · doi:10.1085/jgp.8.6.519 · Cited by 4,416 · see citing works
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
Christofk, H. R., Vander Heiden, M. G., Harris, M. H., Ramanathan, A., Gerszten, R. E., Wei, R., Fleming, M. D., Schreiber, S. L., & Cantley, L. C. (2008) · Nature · doi:10.1038/nature06734 · Cited by 2,820 · see citing works
Self-citationReductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791 · see citing works
Functional genomics reveal that the serine synthesis pathway is essential in breast cancer
Possemato, R., Marks, K. M., Shaul, Y. D., Pacold, M. E., Kim, D., Birsoy, K., Sethumadhavan, S., Woo, H.-K., Jang, H. G., Jha, A. K., et al. (2011) · Nature · doi:10.1038/nature10350 · Cited by 1,683 · see citing works
Self-citationPyruvate Kinase M2 Is a PHD3-Stimulated Coactivator for Hypoxia-Inducible Factor 1
Luo, W., Hu, H., Chang, R., Zhong, J., Knabel, M., O'Meally, R., Cole, R. N., Pandey, A., & Semenza, G. L. (2011) · Cell · doi:10.1016/j.cell.2011.03.054 · Cited by 1,463 · see citing works
Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer
DeBerardinis, R. J., & Cheng, T. (2010) · Oncogene · doi:10.1038/onc.2009.358 · Cited by 1,365 · see citing works
Reductive carboxylation supports growth in tumour cells with defective mitochondria
Mullen, A. R., Wheaton, W. W., Jin, E. S., Chen, P.-H., Sullivan, L. B., Cheng, T., Yang, Y., Linehan, W. M., Chandel, N. S., & DeBerardinis, R. J. (2012) · Nature · doi:10.1038/nature10642 · Cited by 1,328 · see citing works
Anastasiou, D., Poulogiannis, G., Asara, J. M., Boxer, M. B., Jiang, J., Shen, M., Bellinger, G., Sasaki, A. T., Locasale, J. W., Auld, D. S., et al. (2011) · Science · doi:10.1126/science.1211485 · Cited by 1,196 · see citing works
Self-citationPhosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis
Locasale, J. W., Grassian, A. R., Melman, T., Lyssiotis, C. A., Mattaini, K. R., Bass, A. J., Heffron, G., Metallo, C. M., Muranen, T., Sharfi, H., et al. (2011) · Nature Genetics · doi:10.1038/ng.890 · Cited by 1,120 · see citing works
Self-citationNuclear PKM2 regulates β-catenin transactivation upon EGFR activation
Yang, W., Xia, Y., Ji, H., Zheng, Y., Liang, J., Huang, W., Gao, X., Aldape, K., & Lu, Z. (2011) · Nature · doi:10.1038/nature10598 · Cited by 1,033 · see citing works
Pyruvate kinase M2 is a phosphotyrosine-binding protein
Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M., & Cantley, L. C. (2008) · Nature · doi:10.1038/nature06667 · Cited by 995 · see citing works
Self-citationTyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth
Hitosugi, T., Kang, S., Vander Heiden, M. G., Chung, T.-W., Elf, S., Lythgoe, K., Dong, S., Lonial, S., Wang, X., Chen, G. Z., et al. (2009) · Science Signaling · doi:10.1126/scisignal.2000431 · Cited by 784 · see citing works
Self-citationPyruvate Kinase M2 Regulates Gene Transcription by Acting as a Protein Kinase
Gao, X., Wang, H., Yang, J. J., Liu, X., & Liu, Z.-R. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.01.001 · Cited by 772 · see citing works
Ye, J., Kumanova, M., Hart, L. S., Sloane, K. L., Zhang, H., Panis, D. N. D., Bobrovnikova-Marjon, E. V., Diehl, J. A., Ron, D., & Koumenis, C. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.81 · Cited by 709 · see citing works
Discovering statistically significant pathways in expression profiling studies
Tian, L., Greenberg, S. A., Kong, S. W., Altschuler, J., Kohane, I. S., & Park, P. J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506577102 · Cited by 649 · see citing works
Lv, L., Dong, L., Zhao, D., Lin, R., Chu, Y., Zhang, H., Zha, Z., Liu, Y., Li, Z., Xu, Y., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.04.025 · Cited by 605 · see citing works
Noguchi, T., Inoue, H., & Tanaka, T. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)67091-7 · Cited by 544 · see citing works
Clower, C. V., Chatterjee, D., Wang, Z., Cantley, L. C., Vander Heiden, M. G., & Krainer, A. R. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914845107 · Cited by 424 · see citing works
Self-citationStructural Basis for Tumor Pyruvate Kinase M2 Allosteric Regulation and Catalysis ,
Dombrauckas, J. D., Santarsiero, B. D., & Mesecar, A. D. (2005) · Biochemistry · doi:10.1021/bi0474923 · Cited by 414 · see citing works
Fuhrer, T., Heer, D., Begemann, B., & Zamboni, N. (2011) · Analytical Chemistry · doi:10.1021/ac201267k · Cited by 407 · see citing works
Pegaspargase: a review of clinical studies
Graham, M. (2003) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(03)00110-8 · Cited by 322 · see citing works
Metabolic Pathway Alterations that Support Cell ProliferationPreprint
Heiden, M. G. V., Lunt, S. Y., Dayton, T. L., Fiske, B. P., Israelsen, W. J., Mattaini, K. R., Vokes, N. I., Stephanopoulos, G. N., Cantley, L. C., Metallo, C. M., et al. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2012.76.010900 · Cited by 300 · see citing works
Self-citationL-serine in disease and development.
de Koning, T. D., Snell, K., Durán, M., Berger, R., Poll-The, B., & Surtees, R. (2003) · Biochemical Journal · doi:10.1042/bj20021785 · Cited by 287 · see citing works
Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis
Pollari, S., Käkönen, S.-M., Edgren, H., Wolf, M., Kohonen, P., Sara, H., Guise, T., Nees, M., & Kallioniemi, O. (2011) · Breast Cancer Research and Treatment · doi:10.1007/s10549-010-0848-5 · Cited by 269 · see citing works
EIGENBRODT, E., Reinacher, M., Scheefers-Borchel, U., SCHEEFERS, H., & Friis, R. R. (1992) · PubMed · Cited by 210 · see citing works
Ashizawa, K., Willingham, M. C., Liang, C. M., & Cheng, S. Y. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)55378-3 · Cited by 172 · see citing works
Jousse, C., Deval, C., Maurin, A., Parry, L., Chérasse, Y., Chaveroux, C., LeFloch, R., Lenormand, P., Bruhat, A., & Fafournoux, P. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611723200 · Cited by 163 · see citing works
Boxer, M. B., Jiang, J., Heiden, M. G. V., Shen, M., Skoumbourdis, A. P., Southall, N. T., Veith, H., Leister, W., Austin, C. P., Park, H. W., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm901577g · Cited by 159 · see citing works
Self-citationPyruvate kinase type M2: a crossroad in the tumor metabolome
Mazurek, S., Grimm, H., Boschek, C. B., Vaupel, P. W., & EIGENBRODT, E. (2002) · British Journal Of Nutrition · doi:10.1079/bjn2001454 · Cited by 159 · see citing works
Stark, R., Pasquel, F., Turcu, A., Pongratz, R. L., Roden, M., Cline, G., Shulman, G., & Kibbey, R. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.011775 · Cited by 146 · see citing works
Jiang, J., Boxer, M. B., Heiden, M. G. V., Shen, M., Skoumbourdis, A. P., Southall, N. T., Veith, H., Leister, W., Austin, C. P., Park, H. W., et al. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.04.015 · Cited by 127 · see citing works
Self-citationPurification and properties of mitochondrial serine hydroxymethyltransferase.
Schirch, L., & Peterson, D. (1980) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)43903-3 · Cited by 109 · see citing works
Genetic selection for enhanced serine metabolism in cancer development
Locasale, J. W., & Cantley, L. C. (2011) · Cell Cycle · doi:10.4161/cc.10.22.18224 · Cited by 42 · see citing works
Self-citationInhibition of chicken pyruvate kinases by amino acids
Ibsen, K. H., & Marles, S. W. (1976) · Biochemistry · doi:10.1021/bi00650a018 · Cited by 40 · see citing works
VANVEELEN, C. (1977) · The Lancet · doi:10.1016/s0140-6736(77)90308-7 · Cited by 20 · see citing works
Flagged first, then by citations
2 of the 41 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Serine, glycine and one-carbon units: cancer metabolism in full circle
Locasale, J. W. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3557 · Cited by 1,671 · see citing works
Fueling Immunity: Insights into Metabolism and Lymphocyte Function
Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G. (2013) · Science · doi:10.1126/science.1242454 · Cited by 1,363 · see citing works
Molecular targeted therapy: Treating cancer with specificity
Lee, Y. T., Tan, Y. J., & Oon, C. E. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.07.034 · Cited by 1,079 · see citing works
Serine and one-carbon metabolism in cancer
Yang, M., & Vousden, K. H. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.81 · Cited by 992 · see citing works
Targeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971 · see citing works
Structure and dynamics of molecular networks: A novel paradigm of drug discovery
Csermely, P., Korcsmáros, T., Kiss, H., London, G., & Nussinov, R. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.01.016 · Cited by 889 · see citing works
Navigating metabolic pathways to enhance antitumour immunity and immunotherapy
Li, X., Wenes, M., Romero, P. J., Huang, S. C., Fendt, S., & Ho, P. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0203-7 · Cited by 745 · see citing works
Metabolic targets for cancer therapy
Galluzzi, L., Kepp, O., Heiden, M. G. V., & Kroemer, G. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4145 · Cited by 705 · see citing works
Metabolites and the Tumour Microenvironment: From Cellular Mechanisms to Systemic Metabolism
Elia, I., & Haigis, M. C. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00317-z · Cited by 651 · see citing works
Pyruvate kinase: Function, regulation and role in cancer
Israelsen, W. J., & Heiden, M. G. V. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.08.004 · Cited by 593 · see citing works
PKM2, cancer metabolism, and the road ahead
Dayton, T. L., Jacks, T., & Vander Heiden, M. G. (2016) · The EMBO Reports · doi:10.15252/embr.201643300 · Cited by 515 · see citing works
Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis
Zahra, K., Dey, T., Ashish, Mishra, S. P., & Pandey, U. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00159 · Cited by 507 · see citing works
Qi, W., Keenan, H. A., Li, Q., Ishikado, A., Kannt, A., Sadowski, T., Yorek, M. A., Wu, I., Lockhart, S. M., Coppey, L. J., et al. (2017) · Nature Medicine · doi:10.1038/nm.4328 · Cited by 482 · see citing works
Altered metabolite levels in cancer: implications for tumour biology and cancer therapy
Sullivan, L. B., Gui, D. Y., & Heiden, M. G. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.85 · Cited by 406 · see citing works
The importance of serine metabolism in cancer
Mattaini, K. R., Sullivan, M. R., & Heiden, M. G. V. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201604085 · Cited by 409 · see citing works
Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect
Sun, L., Suo, C., Li, S., Zhang, H., & Gao, P. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.06.005 · Cited by 366 · see citing works
PKM2 contributes to cancer metabolism
Wong, N., Ojo, D., Yan, J., & Tang, D. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.01.031 · Cited by 348 · see citing works
Mullarky, E., Lucki, N. C., Beheshti Zavareh, R., Anglin, J. L., Gomes, A. P., Nicolay, B. N., Wong, J. C. Y., Christen, S., Takahashi, H., Singh, P. K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521548113 · Cited by 333 · see citing works
Self-citationPKM2 and cancer: The function of PKM2 beyond glycolysis
Dong, G., Mao, Q., XIA, W., Xu, Y., Wang, J., Xu, L., & JIANG, F. (2016) · Oncology Letters · doi:10.3892/ol.2016.4168 · Cited by 325 · see citing works
Self-citationDysregulated metabolism contributes to oncogenesis
Hirschey, M. D., DeBerardinis, R. J., Diehl, A. M., Drew, J. E., Frezza, C., Green, M. F., Jones, L. W., Ko, Y. H., Le, A., Lea, M. A., et al. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.10.002 · Cited by 306 · see citing works
ROS homeostasis and metabolism: a critical liaison for cancer therapy
Kim, J., Kim, J., & Bae, J. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.119 · Cited by 295 · see citing works
The ins and outs of serine and glycine metabolism in cancer
Geeraerts, S. L., Heylen, E., Keersmaecker, K. D., & Kampen, K. R. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00329-9 · Cited by 250 · see citing works
PKM2, a Central Point of Regulation in Cancer Metabolism
Wong, N., Melo, J. D., & Tang, D. (2013) · International Journal of Cell Biology · doi:10.1155/2013/242513 · Cited by 243 · see citing works
The Warburg effect: Evolving interpretations of an established concept
Chen, X., Qian, Y., & Wu, S. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.08.027 · Cited by 230 · see citing works
Protective Factors and the Pathogenesis of Complications in Diabetes
Yu, M. G., Gordin, D., Fu, J., Park, K., Li, Q., & King, G. L. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnad030 · Cited by 239 · see citing works
Méndez‐Lucas, A., Hyroššová, P., Novellasdemunt, L., Viñals, F., & Perales, J. C. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.566927 · Cited by 200 · see citing works
PCK2 activation mediates an adaptive response to glucose depletion in lung cancer
Leithner, K., Hrzenjak, A., Trötzmüller, M., Moustafa, T., Köfeler, H. C., Wohlkoenig, C., Stacher, E., Lindenmann, J., Harris, A. L., Olschewski, A., et al. (2014) · Oncogene · doi:10.1038/onc.2014.47 · Cited by 201 · see citing works
Fendt, S., Bell, E. L., Keibler, M. A., Davidson, S. M., Wirth, G. J., Fiske, B. P., Mayers, J. R., Schwab, M. G., Bellinger, G., Csibi, A., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-0080 · Cited by 196 · see citing works
Self-citationThe multifaceted regulation and functions of PKM2 in tumor progression
Li, Z., Yang, P., & Li, Z. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.07.008 · Cited by 175 · see citing works
Pyruvate Kinase M2: A Potential Target for Regulating Inflammation
Alves-Filho, J. C., & Pålsson‐McDermott, E. M. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00145 · Cited by 172 · see citing works
Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes
Schreiber, S. L., Kotz, J., Li, M., Aubé, J., Austin, C. P., Reed, J. C., Rosen, H., White, E. L., Sklar, L. A., Lindsley, C. W., et al. (2015) · Cell · doi:10.1016/j.cell.2015.05.023 · Cited by 168 · see citing works
Kremer, J. C., Prudner, B. C., Lange, S. E. S., Bean, G. R., Schultze, M., Brashears, C. B., Radyk, M. D., Redlich, N. J., Tzeng, S., Kami, K., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2016.12.077 · Cited by 160 · see citing works
Li, S., Swanson, S. K., Gogol, M., Florens, L. A., Washburn, M. P., Workman, J. L., & Suganuma, T. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.09.024 · Cited by 155 · see citing works
Kung, C. K.-H., Hixon, J., Kosinski, P. A., Cianchetta, G., Histen, G., Chen, Y., Hill, C., Größ, S., Si, Y., Johnson, K. R., et al. (2017) · Blood · doi:10.1182/blood-2016-11-753525 · Cited by 133 · see citing works
Self-citationStructural insight into mechanisms for dynamic regulation of PKM2
Wang, P., Sun, C., Zhu, T., & Xu, Y. (2015) · Protein & Cell · doi:10.1007/s13238-015-0132-x · Cited by 127 · see citing works
ASO-Based PKM Splice-Switching Therapy Inhibits Hepatocellular Carcinoma Growth
Ma, W. K., Voss, D. M., Scharner, J., Costa, A. S. H., Lin, K., Jeon, H. Y., Wilkinson, J. E., Jackson, M., Rigo, F., Bennett, C. F., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-0948 · Cited by 124 · see citing works
Advances in high‐throughput mass spectrometry in drug discovery
Dueñas, M. E., Heap, R. E., Leveridge, M. V., Annan, R. S., Büttner, F. H., & Trost, M. (2022) · EMBO Molecular Medicine · doi:10.15252/emmm.202114850 · Cited by 124 · see citing works
Allosteric Regulation of PKM2 Allows Cellular Adaptation to Different Physiological States
Gui, D. Y., Lewis, C. A., & Heiden, M. G. V. (2013) · Science Signaling · doi:10.1126/scisignal.2003925 · Cited by 122 · see citing works
Crosstalk between the Warburg effect, redox regulation and autophagy induction in tumourigenesis
Gwangwa, M. V., Joubert, A. M., & Visagie, M. H. (2018) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-018-0088-y · Cited by 117 · see citing works
Targeting Cancer Metabolism - Revisiting the Warburg Effects
Tran, Q., Lee, H., Park, J., Kim, S., & Park, J. (2016) · Toxicological Research · doi:10.5487/tr.2016.32.3.177 · Cited by 109 · see citing works
Lack of Evidence for PKM2 Protein Kinase Activity
Hosios, A. M., Fiske, B. P., Gui, D. Y., & Heiden, M. G. V. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.07.013 · Cited by 108 · see citing works
Esaki, K., Sayano, T., Sonoda, C., Akagi, T., Suzuki, T., Ogawa, T., Okamoto, M., Yoshikawa, T., Hirabayashi, Y., & Furuya, S. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.603860 · Cited by 98 · see citing works
An update on therapeutic opportunities offered by cancer glycolytic metabolism
Granchi, C., Fancelli, D., & Minutolo, F. (2014) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2014.09.041 · Cited by 91 · see citing works
Méndez‐Lucas, A., Li, X., Hu, J., Che, L., Song, X., Jia, J., Wang, J., Xie, C., Driscoll, P. C., Tschaharganeh, D. F., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0498 · Cited by 89 · see citing works
Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth
Chen, J., Chung, F., Yang, G., Pu, M., Gao, H., Jiang, W., Yin, H., Capka, V., Kasibhatla, S., Laffitte, B., et al. (2013) · Oncotarget · doi:10.18632/oncotarget.1540 · Cited by 82 · see citing works
Coassolo, S., Davidson, G., Négroni, L., Gambi, G., Daujat, S., Romier, C., & Davidson, I. (2021) · Nature Communications · doi:10.1038/s41467-021-21960-4 · Cited by 79 · see citing works
Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway
Soflaee, M. H., Kesavan, R., Sahu, U., Tasdogan, A., Villa, E., Djabari, Z., Cai, F., Tran, D. H., Vu, H., Ali, E. S., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30362-z · Cited by 81 · see citing works
Novel drugs that target the metabolic reprogramming in renal cell cancer
van der Mijn, J. C., Panka, D. J., Geissler, A. K., Verheul, H. M. W., & Mier, J. W. (2016) · Cancer & Metabolism · doi:10.1186/s40170-016-0154-8 · Cited by 81 · see citing works
High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells
Jeong, S., Savino, A. M., Chirayil, R., Barin, E., Cheng, Y., Park, S., Schurer, A., Mullarky, E., Cantley, L. C., Kharas, M. G., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.12.005 · Cited by 76 · see citing works
Self-citationMitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias
Al-Samkari, H. T., & van Beers, E. J. (2021) · Therapeutic Advances in Hematology · doi:10.1177/20406207211066070 · Cited by 80 · see citing works
Glucose addiction in cancer therapy: advances and drawbacks
Granja, S., Pinheiro, C. M., Reis, R. M., Martinho, O., & Baltazar, F. (2015) · Current Drug Metabolism · doi:10.2174/1389200216666150602145145 · Cited by 75 · see citing works
Mechanism of PKM2 affecting cancer immunity and metabolism in Tumor Microenvironment
Chen, M., Liu, H., Li, Z., Ming, A. L., & Chen, H. (2021) · Journal of Cancer · doi:10.7150/jca.54430 · Cited by 73 · see citing works
Pharmacologic Activation of PKM2 Slows Lung Tumor Xenograft Growth
Parnell, K. M., Foulks, J. M., Nix, R. N., Clifford, A., Bullough, J., LUO, B. H., Senina, A. V., Vollmer, D., Liu, J., McCarthy, V., et al. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0026 · Cited by 72 · see citing works
Wiese, E. K., Hitosugi, S., Loa, S. T., Sreedhar, A., Andres‐Beck, L. G., Kurmi, K., Pang, Y., Karnitz, L. M., Gonsalves, W. I., & Hitosugi, T. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00424-5 · Cited by 65 · see citing works
McDonnell, S. R. P., Hwang, S. R., Rolland, D. C. M., Murga‐Zamalloa, C., Basrur, V., Conlon, K. P., Fermin, D., Wolfe, T., Raskind, A. B., Ruan, C., et al. (2013) · Blood · doi:10.1182/blood-2013-01-482026 · Cited by 66 · see citing works
An allostatic mechanism for M2 pyruvate kinase as an amino-acid sensor
Yuan, M., McNae, I. W., Chen, Y., Blackburn, E. A., Wear, M. A., Michels, P. A. M., Fothergill‐Gilmore, L. A., Hupp, T. R., & Walkinshaw, M. D. (2018) · Biochemical Journal · doi:10.1042/bcj20180171 · Cited by 66 · see citing works
The PHGDH enigma: Do cancer cells only need serine or also a redox modulator?
Li, A. M., & Ye, J. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.01.036 · Cited by 65 · see citing works
Role of PKM2-Mediated Immunometabolic Reprogramming on Development of Cytokine Storm
Liu, Z., Le, Y., Chen, H., Zhu, J., & Lu, D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.748573 · Cited by 66 · see citing works
Zhu, J., Chen, H., Le, Y., Guo, J., Liu, Z., Dou, X., & Lu, D. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1009229 · Cited by 63 · see citing works
Role of PKM2 in directing the metabolic fate of glucose in cancer: a potential therapeutic target
van Niekerk, G., & Engelbrecht, A. (2018) · Cellular Oncology · doi:10.1007/s13402-018-0383-7 · Cited by 57 · see citing works
Activators of PKM2 in Cancer Metabolism
Warner, S. L., Carpenter, K. J., & Bearss, D. J. (2014) · Future Medicinal Chemistry · doi:10.4155/fmc.14.70 · Cited by 57 · see citing works
Filipp, F. V. (2013) · Journal of Carcinogenesis · doi:10.4103/1477-3163.115423 · Cited by 57 · see citing works
Guo, J., Xue, Q., Liu, K., Ge, W., Liu, W., Wang, J., Zhang, M., Li, Q., Cai, D. D., Shan, C., et al. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00993 · Cited by 51 · see citing works
Self-citationTargeting Cell Metabolism as Cancer Therapy
Ngoi, N. Y. L., Eu, J. Q., Hirpara, J. L., Wang, L., Lim, J. S. J., Lee, S. C., Lim, Y., Pervaiz, S., Goh, B. C., & Wong, A. L. A. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7947 · Cited by 51 · see citing works
Zhang, Y., Liu, B., Wu, X., Li, R., Ning, X., Liu, Y., Liu, Z., Ge, Z., Li, R., & Yin, Y. (2015) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2015.05.041 · Cited by 49 · see citing works
Rathod, B., Chak, S., Patel, S., & Shard, A. (2021) · RSC Medicinal Chemistry · doi:10.1039/d1md00045d · Cited by 48 · see citing works
The Role of Pyruvate Kinase M2 in Cancer Metabolism
Liu, V. M., & Heiden, M. G. V. (2015) · Brain Pathology · doi:10.1111/bpa.12311 · Cited by 49 · see citing works
Fu, J., Shinjo, T., Li, Q., St-Louis, R., Park, K., Yu, M. G., Yokomizo, H., Simão, F., Huang, Q., Wu, I., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.155260 · Cited by 48 · see citing works
Revisiting the Warburg Effect: Diet‐Based Strategies for Cancer Prevention
Tran, Q., Lee, H., Kim, C., Kong, G., Gong, N., Kwon, S. H., Park, J., Kim, S., & Park, J. (2020) · BioMed Research International · doi:10.1155/2020/8105735 · Cited by 47 · see citing works
A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2
Arora, S., Joshi, G., Chaturvedi, A., Heuser, M., Patil, S. N., & Kumar, R. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00981 · Cited by 46 · see citing works
Energy Metabolism on Mitochondrial Maturation and Its Effects on Cardiomyocyte Cell Fate
Persad, K. L., & Lopaschuk, G. D. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.886393 · Cited by 47 · see citing works
Targeting pyruvate kinase muscle isoform 2 (PKM2) in cancer: What do we know so far?
Chhipa, A. S., & Patel, S. S. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119694 · Cited by 44 · see citing works
Action at a Distance: Allostery and the Development of Drugs to Target Cancer Cell Metabolism
DeLaBarre, B., Hurov, J., Cianchetta, G., Murray, S., & Dang, L. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.08.007 · Cited by 44 · see citing works
Self-citationStress eating and tuning out: Cancer cells re-wire metabolism to counter stress
Stine, Z. E., & Dang, C. V. (2013) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2013.844093 · Cited by 43 · see citing works
NRF2 Rewires Cellular Metabolism to Support the Antioxidant Response
Lin, T.-Y., Cantley, L. C., & DeNicola, G. M. (2016) · InTech eBooks · doi:10.5772/65141 · Cited by 43 · see citing works
Self-citationTumor aerobic glycolysis: new insights into therapeutic strategies with targeted delivery
Talekar, M., Boreddy, S. R., Singh, A., & Amiji, M. M. (2014) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2014.912270 · Cited by 42 · see citing works
CARM1 suppresses de novo serine synthesis by promoting PKM2 activity
Abeywardana, T., Oh, M., Jiang, L., Yang, Y., Song, J., Song, J., & Yang, Y. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.004512 · Cited by 41 · see citing works
Inhibitors of glucose transport and glycolysis as novel anticancer therapeutics
Qian, Y. (2014) · World Journal of Translational Medicine · doi:10.5528/wjtm.v3.i2.37 · Cited by 40 · see citing works
Almouhanna, F., Blagojevic, B., Can, S., Ghanem, A., & Wölfl, S. (2021) · Cancer & Metabolism · doi:10.1186/s40170-021-00239-8 · Cited by 40 · see citing works
Targeting allosteric regulation of cancer metabolism
Kremer, D. M., & Lyssiotis, C. A. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-00997-6 · Cited by 40 · see citing works
Synthetic Approaches to Piperazine-Containing Drugs Approved by FDA in the Period of 2011–2023
Romanelli, M. N., Braconi, L., Gabellini, A., Manetti, D., Marotta, G., & Teodori, E. (2023) · Molecules · doi:10.3390/molecules29010068 · Cited by 39 · see citing works
Brown, D. M., Williams, H., Ryan, K. J. P., Wilson, T. L., Daniel, Z. C. T. R., Mareko, M. H. D., Emes, R. D., Harris, D. W., Jones, S., Wattis, J. A. D., et al. (2016) · Scientific Reports · doi:10.1038/srep28693 · Cited by 39 · see citing works
Mattaini, K. R., Brignole, E. J., Kini, M., Davidson, S. M., Fiske, B. P., Drennan, C. L., & Vander Heiden, M. G. (2015) · Cancer & Metabolism · doi:10.1186/s40170-015-0131-7 · Cited by 38 · see citing works
Lin, H., Han, H., Yang, M., Wen, Z., Chen, Q., Ma, Y., Wang, X., Wang, C., Yin, T., Wang, X., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115166 · Cited by 38 · see citing works
Self-citationPyruvate Kinase M2: a Metabolic Bug in Re-Wiring the Tumor Microenvironment
Rihan, M., Nalla, L. V., Dharavath, A., Shard, A., Kalia, K., & Khairnar, A. (2019) · Cancer Microenvironment · doi:10.1007/s12307-019-00226-0 · Cited by 36 · see citing works
Metabolic Strategies for Inhibiting Cancer Development
Icard, P., Loi, M., Wu, Z., Ginguay, A., Lincet, H., Robin, E., Coquerel, A., Berzan, D., Fournel, L., & Alifano, M. (2020) · Advances in Nutrition · doi:10.1093/advances/nmaa174 · Cited by 36 · see citing works
Free Glycine Accelerates the Autoproteolytic Activation of Human Asparaginase
Su, Y., Karamitros, C. S., Nomme, J., McSorley, T., Konrad, M., & Lavie, A. (2013) · Chemistry & Biology · doi:10.1016/j.chembiol.2013.03.006 · Cited by 36 · see citing works
Biochemical and structural insights into how amino acids regulate pyruvate kinase muscle isoform 2
Nandi, S., & Dey, M. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.013030 · Cited by 35 · see citing works
Kim, D. J., Park, Y. S., Kim, N. D., Min, S. H., You, Y.-M., Jung, Y., Koo, H., Noh, H., Kim, J., Park, K. C., et al. (2015) · Molecules and Cells · doi:10.14348/molcells.2015.2314 · Cited by 34 · see citing works
Expanded Cellular Amino Acid Pools Containing Phosphoserine, Phosphothreonine, and Phosphotyrosine
Steinfeld, J. B., Aerni, H. R., Rogulina, S., Liu, Y., & Rinehart, J. (2014) · ACS Chemical Biology · doi:10.1021/cb5000532 · Cited by 34 · see citing works
Bahiraii, S., Brenner, M., Yan, F., Weckwerth, W., & Heiß, E. H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.935692 · Cited by 33 · see citing works
Li, A. M., & Ye, J. (2023) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-062822-120857 · Cited by 31 · see citing works
Liu, B., Yuan, X., Xu, B., Zhang, H., Li, R., Wang, X., Ge, Z., & Li, R. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.03.003 · Cited by 31 · see citing works
Self-citationAyyildiz, M., Çeliker, S., Ozhelvaci, F., & Akten, E. D. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.00088 · Cited by 32 · see citing works
PKM2 activation sensitizes cancer cells to growth inhibition by 2-deoxy-D-glucose
Tee, S. S., Park, J. M., Hurd, R. E., Brimacombe, K. R., Boxer, M. B., Massoud, T. F., Rutt, B. K., & Spielman, D. M. (2017) · Oncotarget · doi:10.18632/oncotarget.19630 · Cited by 32 · see citing works
Chen, T., Wang, H., Liu, J.-S., Cheng, H.-H., Hsu, S.-C., Wu, M.-C., Lu, C., Wu, Y.-F., Wu, J.-W., Liu, Y.-Y., et al. (2019) · Communications Biology · doi:10.1038/s42003-019-0343-4 · Cited by 30 · see citing works
Role of Pyruvate Kinase M2 (PKM2) in Cardiovascular Diseases
Rihan, M., & Sharma, S. S. (2022) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-022-10321-1 · Cited by 30 · see citing works
Matsui, Y., Yasumatsu, I., Asahi, T., Kitamura, T., Kanai, K., Ubukata, O., Hayasaka, H., Takaishi, S., Hanzawa, H., & KATAKURA, S. (2017) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2017.05.004 · Cited by 31 · see citing works
Nuclear PKM2: a signal receiver, a gene programmer, and a metabolic modulator
Chen, T., Wu, C., Hung, M., Wang, W., & Kung, H.-J. (2025) · Journal of Biomedical Science · doi:10.1186/s12929-025-01170-6 · Cited by 29 · see citing works
Anti-tumor Drug Targets Analysis: Current Insight and Future Prospect
Wang, S., Zhou, D., Xu, Z., Song, J., Qian, X., Lv, X., & Luan, J. (2019) · Current Drug Targets · doi:10.2174/1389450120666190402145325 · Cited by 29 · see citing works
Self-citation
- Authors
- Kung, C., Hixon, J., Choe, S., Marks, K., Gross, S., Murphy, E., DeLaBarre, B., Cianchetta, G., Sethumadhavan, S., Wang, X., Yan, S., Gao, Y., Fang, C., Wei, W., Jiang, F., Wang, S., Qian, K., Saunders, J., Driggers, E., Woo, H. K., Kunii, K., Murray, S., Yang, H., Yen, K., Liu, W., Cantley, L. C., Vander Heiden, M. G., Su, S. M., Jin, S., Salituro, F. G., & Dang, L.
- Affiliations
- Agios Pharmaceuticals (United States) (US)
- Schrodinger (United States) (US)
- Viva Biotech (China) (CN)
- Beth Israel Deaconess Medical Center (US)
- ORCID
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 19
- Issue
- 9
- Pages
- 1187-1198
- ISSN
- 1074-5521 (ISSN-L)
- PMC
- PMC3775715
- OpenAlex
- W1598610496
- Cited by
- 192
- References
- 41
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 12 · 2023: 16 · 2022: 13 · 2021: 25 · 2020: 9 · 2019: 9 · 2018: 16 · 2017: 14 · 2016: 15 · 2015: 12 · 2014: 14 · 2013: 16 · 2012: 2
- FWCI
- 4.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Damon Runyon Cancer Research Foundation
- Wellcome Trust
- Agios Pharmaceuticals
- National Institute of General Medical Sciences (R01GM56302, R01GM056203)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- PKM2, small molecule activators, allosteric activation, aerobic glycolysis, cancer metabolism, serine biosynthesis, metabolic reprogramming, nutritional stress, metabolic flexibility, cell proliferation
- MeSH terms
- Thyroid Hormone-Binding Proteins, Allosteric Site, Carrier Proteins, Dose-Response Relationship, Drug, Humans, Membrane Proteins, Models, Molecular, Serine, Structure-Activity Relationship, Thyroid Hormones, Tumor Cells, Cultured, Molecular Structure, Cell Proliferation, Small Molecule Libraries
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
