Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERK-dependent necroptosis
Open accessAbstract
Abstract The association between lower circulating adiponectin (APN) levels and the development of pancreatic cancer has been reported. However, the effect of APN on the growth and survival of pancreatic cancer cells remains elusive. Here, we investigate the effects of the anti-diabetic APN receptor (AdipoR) agonist AdipoRon and APN on human pancreatic cancer cells. We found that AdipoRon, but not APN, induces MIAPaCa-2 cell death, mainly through necroptosis. Mechanistically, although both AdipoRon and APN activate AMPK and p38 MAPK in an AdipoR-dependent manner that elicits survival signals, only AdipoRon induces rapid mitochondrial dysfunction through mitochondrial Ca2+ overload, followed by superoxide production via RIPK1 and ERK1/2 activation. Oral administration of AdipoRon suppresses MIAPaCa-2 tumour growth without severe adverse effects and kills cancer cells isolated from patients with pancreatic cancer. Thus, AdipoRon could be a therapeutic agent against pancreatic cancer as well as diabetes.
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?
AdipoRon's beneficial effects have been demonstrated in other non-metabolic conditions such as cancer, systemic sclerosis, depression, anxiety, PTSD, and cerebral ischemia.
“Since then, its beneficial effects have also been demonstrated in other non-metabolic conditions such as cancer [139,140], systemic sclerosis [141], depression [107], anxiety [142], post-traumatic stress disorder [143], and cerebral ischemia [144,145].”
From Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together? (2020) · cites this paper as [140]
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
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691 · see citing works
Rahib, L., Smith, B. D., Aizenberg, R., Rosenzweig, A. B., Fleshman, J. M., & Matrisian, L. M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0155 · Cited by 7,094 · see citing works
Yamauchi, T., Kamon, J., Waki, H., Terauchi, Y., Kubota, N., Hara, K., Mori, Y., Ide, T., Murakami, K., Tsuboyama-Kasaoka, N., et al. (2001) · Nature Medicine · doi:10.1038/90984 · Cited by 4,915 · see citing works
Weyer, C., Funahashi, T., Tanaka, S., Hotta, K., Matsuzawa, Y., Pratley, R. E., & Tataranni, P. A. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.5.7463 · Cited by 3,541 · see citing works
European Guidelines for Obesity Management in Adults
Yumuk, V., Tsigos, C., Fried, M., Schindler, K., Busetto, L., Micic, D., & Toplak, H. (2015) · Obesity Facts · doi:10.1159/000442721 · Cited by 3,432 · see citing works
A Novel Serum Protein Similar to C1q, Produced Exclusively in Adipocytes
Scherer, P. E., Williams, S. P., Fogliano, M., Baldini, G., & Lodish, H. F. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.45.26746 · Cited by 3,238 · see citing works
Adipocytokines: mediators linking adipose tissue, inflammation and immunity
Tilg, H., & Moschen, A. R. (2006) · Nature reviews. Immunology · doi:10.1038/nri1937 · Cited by 3,195 · see citing works
Cloning of adiponectin receptors that mediate antidiabetic metabolic effects
Yamauchi, T., Kamon, J., Ito, Y., Tsuchida, A., Yokomizo, T., Kita, S., Sugiyama, T., Miyagishi, M., Hara, K., Tsunoda, M., et al. (2003) · Nature · doi:10.1038/nature01705 · Cited by 3,176 · see citing works
Adiponectin and Adiponectin Receptors
Kadowaki, T., & Yamauchi, T. (2005) · Endocrine Reviews · doi:10.1210/er.2005-0005 · Cited by 2,634 · see citing works
The adipocyte-secreted protein Acrp30 enhances hepatic insulin action
Berg, A. H., Combs, T. P., Du, X., Brownlee, M., & Scherer, P. E. (2001) · Nature Medicine · doi:10.1038/90992 · Cited by 2,526 · see citing works
AdipoQ Is a Novel Adipose-specific Gene Dysregulated in Obesity
Hu, E., Liang, P., & Spiegelman, B. M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.18.10697 · Cited by 2,239 · see citing works
Maeda, K., Okubo, K., Shimomura, I., Funahashi, T., Matsuzawa, Y., & Matsubara, K. (1996) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1996.0587 · Cited by 2,081 · see citing works
Isolation and Characterization of GBP28, a Novel Gelatin-Binding Protein Purified from Human Plasma
Nakano, Y., Tobe, T., Choi-Miura, N.-H., Mazda, T., & Tomita, M. (1996) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a021483 · Cited by 915 · see citing works
A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity
Okada-Iwabu, M., Yamauchi, T., Iwabu, M., Honma, T., Hamagami, K.-I., Matsuda, K., Yamaguchi, M., Tanabe, H., Kimura-Someya, T., Shirouzu, M., et al. (2013) · Nature · doi:10.1038/nature12656 · Cited by 757 · see citing works
Mitochondrial calcium and the permeability transition in cell death
Lemasters, J. J., Theruvath, T. P., Zhong, Z., & Nieminen, A. (2009) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.06.009 · Cited by 656 · see citing works
Petersen, G. M., Amundadottir, L. T., Fuchs, C. S., Kraft, P., Stolzenberg‐Solomon, R. Z., Jacobs, K. B., Arslan, A. A., Bueno-de-Mesquita, H. B., Gallinger, S., Gross, M. D., et al. (2010) · Nature Genetics · doi:10.1038/ng.522 · Cited by 596 · see citing works
Initiation and execution mechanisms of necroptosis: an overview
Grootjans, S., Vanden Berghe, T., & Vandenabeele, P. (2017) · Cell Death & Differentiation · doi:10.1038/cdd.2017.65 · Cited by 566 · see citing works
Diabetes, pancreatogenic diabetes, and pancreatic cancer
Andersen, D. K., Korc, M., Petersen, G. M., Eibl, G., Li, D., Rickels, M. R., Chari, S. T., & Abbruzzese, J. L. (2017) · Diabetes · doi:10.2337/db16-1477 · Cited by 516 · see citing works
Low Plasma Adiponectin Levels and Risk of Colorectal Cancer in Men: A Prospective Study
Wei, E. K., Giovannucci, E. L., Fuchs, C. S., Willett, W. C., & Mantzoros, C. S. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji376 · Cited by 488 · see citing works
MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism
Mallilankaraman, K. B., Cárdenas, C., Doonan, P. J., Chandramoorthy, H. C. K., Irrinki, K. M., Golenár, T., Csordás, G., Madireddi, P., Yang, J., Müller, M., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2622 · Cited by 487 · see citing works
Adibhatla, R. M., & Hatcher, J. F. (2010) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2668 · Cited by 480 · see citing works
Mitochondrial Ca2+ and apoptosis
Giorgi, C., Baldassari, F., Bononi, A., Bonora, M., Marchi, E. D., Marchi, S., Missiroli, S., Patergnani, S., Rimessi, A., Suski, J. M., et al. (2012) · Cell Calcium · doi:10.1016/j.ceca.2012.02.008 · Cited by 474 · see citing works
Takahashi, N., Duprez, L., Grootjans, S., Cauwels, A., Nerinckx, W., DuHadaway, J. B., Goossens, V, Roelandt, R., Van Hauwermeiren, F., Libert, C., et al. (2012) · Cell Death & Disease · doi:10.1038/cddis.2012.176 · Cited by 465 · see citing works
Crosstalk signaling between mitochondrial Ca2+ and ROS
Robert, F. F. (2009) · Frontiers in bioscience · doi:10.2741/3303 · Cited by 439 · see citing works
Mallilankaraman, K. B., Cárdenas, C., Doonan, P. J., Chandramoorthy, H. C. K., Irrinki, K. M., Golenár, T., Csordás, G., Madireddi, P., Yang, J., Müller, M., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3202 · Cited by 418 · see citing works
Adiponectin receptors: A review of their structure, function and how they work
Yamauchi, T., Iwabu, M., Okada‐Iwabu, M., & Kadowaki, T. (2013) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2013.09.003 · Cited by 355 · see citing works
Role of anti-inflammatory adipokines in obesity-related diseases
Ohashi, K., Shibata, R., Murohara, T., & Ouchi, N. (2014) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2014.03.009 · Cited by 321 · see citing works
FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells
Bell, B. D., Leverrier, S., Weist, B. M., Newton, R. H., Arechiga, A. F., Luhrs, K. A., Morrissette, N. S., & Walsh, C. M. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808597105 · Cited by 290 · see citing works
Plasma Adiponectin Concentrations and Risk of Incident Breast Cancer
Tworoger, S. S., Eliassen, A. H., Kelesidis, T., Colditz, G. A., Willett, W. C., Mantzoros, C. S., & Hankinson, S. E. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-1975 · Cited by 285 · see citing works
MCUR1は細胞代謝を制御するミトコンドリアCa 2MCUR1+ 取込の必須成分である
Mallilankaraman, K. B., Cesar, C., Patrick, J., Harish, C. C., Krishna, M. I., Golenár, T., Gyoergy, C., Madireddi, P., Jun, Y., Müller, M., et al. (2012) · Nature Cell Biology · Cited by 270 · see citing works
p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α
Barger, P. M., Browning, A. C., Garner, A. N., & Kelly, D. P. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105945200 · Cited by 260 · see citing works
Calcium and Mitochondrial Reactive Oxygen Species Generation: How to Read the Facts
Ádám‐Vizi, V., & Starkov, A. A. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100465 · Cited by 250 · see citing works
PPAR and Oxidative Stress: Con() Catenating NRF2 and FOXO
Polvani, S., Tarocchi, M., & Galli, A. (2012) · PPAR Research · doi:10.1155/2012/641087 · Cited by 248 · see citing works
Plasma Adiponectin Levels and Endometrial Cancer Risk in Pre- and Postmenopausal Women
Cust, A. E., Kaaks, R., Friedenreich, C. M., Bonnet, F., Laville, M., Lukanova, A., Rinaldi, S., Dossus, L., Slimani, N., Lundin, E., et al. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-1371 · Cited by 208 · see citing works
Trollinger, D. R., Cascio, W. E., & Lemasters, J. J. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.7042 · Cited by 199 · see citing works
Michalakis, K. G., Williams, C. J., Mitsiades, N., Blakeman, J., Balafouta-Tselenis, S., Giannopoulos, A., & Mantzoros, C. S. (2007) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-06-0621 · Cited by 182 · see citing works
Akimoto, M., Iizuka, M., Kanematsu, R., Yoshida, M., & Takenaga, K. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126605 · Cited by 178 · see citing works
Self-citationSawai, H., & Domae, N. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.06.186 · Cited by 161 · see citing works
Man, K., Ng, K. T., Xu, A., Cheng, Q., Lo, C. M., Xiao, J. W., Sun, B. S., Lim, Z. X. H., Cheung, J. S., Wu, E. X., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1487 · Cited by 134 · see citing works
The role of altered [Ca2+]i regulation in apoptosis, oncosis, and necrosis
Trump, B. F., & Berezesky, I. K. (1996) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/0167-4889(96)00086-9 · Cited by 125 · see citing works
Obesity potentiates the growth and dissemination of pancreatic cancer
Zyromski, N. J., Mathur, A., Pitt, H. A., Wade, T., Wang, S. S., Bhat‐Nakshatri, P., Swartz‐Basile, D. A., & Nakshatri, H. (2009) · Surgery · doi:10.1016/j.surg.2009.02.024 · Cited by 120 · see citing works
A Prospective Study of Plasma Adiponectin and Pancreatic Cancer Risk in Five US Cohorts
Bao, Y., Giovannucci, E. L., Kraft, P. L., Stampfer, M. J., Ogino, S., Ma, J., Buring, J. E., Sesso, H. D., Lee, I.-M. M., Gaziano, J. M., et al. (2012) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djs474 · Cited by 117 · see citing works
Dalamaga, Μ., Migdalis, I. N., Fargnoli, J. L., Papadavid, E., Bloom, E., Mitsiades, N., Καρμανιώλας, Κ., Pelecanos, N., Tseleni‐Balafouta, S., Dionyssiou‐Asteriou, A., et al. (2008) · Cancer Causes & Control · doi:10.1007/s10552-008-9273-z · Cited by 113 · see citing works
McComb, S., Aguadé-Gorgorió, J., Behrmann, L., Marovca, B., Cario, G., Eckert, C., Schrappe, M., Stanulla, M., von Stackelberg, A., Bourquin, J., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad2986 · Cited by 113 · see citing works
Ozaki, T., Yamashita, T., & Ishiguro, S.-I. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2009.10.002 · Cited by 95 · see citing works
Chen, Q., Paillard, M., Gomez, L., Ross, T., Hu, Y., Xu, A., & Lesnefsky, E. J. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.10.037 · Cited by 92 · see citing works
Huang, B., Cheng, X., Wang, D., Peng, M., Xue, Z., Da, Y., Zhang, N., Yao, Z., Li, M., Xu, A., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.1963 · Cited by 88 · see citing works
Lin, C.-Y., Chang, T.-W., Hsieh, W.-H., Hung, M.-C., Lin, I.-H., Lai, S.-C., & Tzeng, Y.-J. (2016) · Cell Death Discovery · doi:10.1038/cddiscovery.2016.65 · Cited by 88 · see citing works
Zhang, M., Harashima, N., Moritani, T., Huang, W., & Harada, M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0127386 · Cited by 84 · see citing works
Prediagnostic Adiponectin Concentrations and Pancreatic Cancer Risk in Male Smokers
Stolzenberg‐Solomon, R. Z., Weinstein, S. J., Pollak, M., Tao, Y., Taylor, P. R., Virtamo, J. R. K., & Albanes, D. (2008) · American Journal of Epidemiology · doi:10.1093/aje/kwn221 · Cited by 70 · see citing works
Chang, M., Chang, Y., Su, T., Yang, W., Chen, C., Tien, Y., Liang, P., Wei, S., & Wong, J. (2007) · Pancreas · doi:10.1097/mpa.0b013e3180547709 · Cited by 69 · see citing works
Grote, V. A., Rohrmann, S., Dossus, L., Nieters, A., Halkjær, J., Tjønneland, A. M., Overvad, K., Stegger, J. G., Chabbert‐Buffet, N., Boutron‐Ruault, M., et al. (2011) · International Journal of Cancer · doi:10.1002/ijc.26244 · Cited by 49 · see citing works
Synthesis and properties of fluorescence probe for detection of peroxides in mitochondria
Shioji, K., Oyama, Y., Okuma, K., & Nakagawa, H. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.05.017 · Cited by 42 · see citing works
Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK
Ying, Y., Ueta, T., Jiang, S., Lin, H., Wang, Y., Vavvas, D. G., Wen, R., Chen, Y., & Luo, Z. (2017) · Oncotarget · doi:10.18632/oncotarget.15825 · Cited by 36 · see citing works
Pezzilli, R., Barassi, A., Romanelli, M. M. C., et al. (2009) · Scandinavian Journal of Gastroenterology · doi:10.3109/00365520903358907 · Cited by 34 · see citing works
Toward a Better Understanding of Pancreatic Ductal Adenocarcinoma
Partensky, C. (2013) · Pancreas · doi:10.1097/mpa.0b013e318288107a · Cited by 32 · see citing works
The mitochondrial Ca 2+ uniporter: regulation by auxiliary subunits and signal transduction pathways
Jhun, B. S., Mishra, J., Monaco, S. A., Fu, D., Jiang, W., Sheu, S., & O‐Uchi, J. (2016) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00319.2015 · Cited by 29 · see citing works
Adiponectin Inhibits Murine Pancreatic Cancer Growth
Kato, M., Watabe, K., Tsujii, M., Funahashi, T., Shimomura, I., & Takehara, T. (2014) · Digestive Diseases and Sciences · doi:10.1007/s10620-014-3175-6 · Cited by 21 · see citing works
Novel strategies for managing pancreatic cancer
Loc, W. S. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i40.14717 · Cited by 19 · see citing works
Antioxidant Stress and Anti-Inflammation of PPARαon Warm Hepatic Ischemia-Reperfusion Injury
Gao, Z., & Li, Y. (2012) · PPAR Research · doi:10.1155/2012/738785 · Cited by 18 · see citing works
Kler, R. S., Sherratt, H. S. A., & Turnbull, D. M. (1992) · Biochemical Medicine and Metabolic Biology · doi:10.1016/0885-4505(92)90018-t · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Abou-Samra, M., Selvais, C. M., Dubuisson, N., & Brichard, S. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072620 · Cited by 72 · see citing works
Gamberi, T., Magherini, F., & Fiaschi, T. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20071544 · Cited by 18 · see citing works
- Authors
- Akimoto, M., Maruyama, R., Kawabata, Y., Tajima, Y., & Takenaga, K.
- Affiliations
- Shimane University (JP)
- Corresponding author
- Takenaga, Keizo
- Venue
- Cell Death & Disease
- Published
- 2018-07-23
- Volume
- 9
- Issue
- 8
- Pages
- 804-804
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC6056513
- OpenAlex
- W2883103051
- Cited by
- 104
- References
- 61
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 12 · 2023: 17 · 2022: 15 · 2021: 13 · 2020: 11 · 2019: 11 · 2018: 2
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (16K10594, 16K21177)
- Shimane University (SUIGANN’ Project)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- AdipoRon, adiponectin, adiponectin receptors, pancreatic cancer, necroptosis, RIPK1, ERK1/2, AMPK, p38 MAPK, superoxide, mitochondrial dysfunction, tumor growth inhibition, MIA PaCa-2 cells
- MeSH terms
- Calcium, Humans, Mitochondria, Pancreatic Neoplasms, Piperidines, Superoxides, Calcium Channels, Signal Transduction, Apoptosis, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, p38 Mitogen-Activated Protein Kinases, Receptor-Interacting Protein Serine-Threonine Kinases, Receptors, Adiponectin
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
