CoChat
Sign Up
Cited by 16

The DOI matches its Crossref record; 13 of the 13 references it cites were found in a registry or an index.

Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells

Kim, Justin, Brunetti, Bryce, Kumar, Ayanesh, Mangla, Ankit, Honda, Kord, Yoshida, Akihiro·2024·Cell Death & Disease
DOI 10.1038/s41419-024-07284-3PMC PMC11655860
Open this paper in CoChat — free account

Abstract

The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses Braf V600E melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent Braf V600E melanoma cells. Upregulated GLS1 expression renders Braf V600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the Braf V600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders Braf V600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced.

Overview

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41419-024-07284-3

Cites

13 of 13 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 KGA expression is increased in palbociclib-induced senescent cells. A–D WM3918 (BrafWTNrasWT), WM3912 (BrafWTNrasWT), A375 (BrafV600ENrasWT), 1205Lu (BrafV600ENrasWT), Skmel28 (BrafV600ENrasWT), Skmel2 (BrafWTNrasQ61R), WM3451 (BrafWTNrasQ61K), and normal human melanocytes (HEMa) were treated with DMSO or palbociclib (1 μM) for 1 day or 8 days. Treated cells were subjected to SA-βgal assay (8 days treatment only) and SA-βgal positive cells were quantified. Data represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). A and RT-qPCR analysis for KGA (B), GAC (C) and GLS2 (D). RT-qPCR data (B–D) were normalized by GAPDH and represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). E 1205Lu and Skmel28 cells treated with DMSO (Control) or palbociclib (1 μM) for 8 days were subjected to western blot for GLS1 and βactin. An arrowhead indicates KGA expression. F 1205Lu cells treated with DMSO (Control) or palbociclib (1 μM) for 1 day or 8 days and 4 clones of 1205Lu palbociclib resistant cells (PR_1, PR_2, PR_3 and PR_4) maintained in the palbociclib-containing medium were harvested and subjected to RT-qPCR analysis for KGA expression. Data were normalized by GAPDH and represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). G 1205Lu, Skmel28 and Skmel2 cells were treated with DMSO or palbociclib for 8 days, and then treated with actinomycin D (0.5 μg/ml) for 2 h. Harvested cells were subjected to RT-qPCR analysis for KGA expression. Data were normalized by GAPDH and represent mean ± SD, p < 0.05 (two-tailed Student’s t-test; n = 3). NS indicates no significance (n = 3).
Fig. 1 KGA expression is increased in palbociclib-induced senescent cells. A–D WM3918 (BrafWTNrasWT), WM3912 (BrafWTNrasWT), A375 (BrafV600ENrasWT), 1205Lu (BrafV600ENrasWT), Skmel28 (BrafV600ENrasWT), Skmel2 (BrafWTNrasQ61R), WM3451 (BrafWTNrasQ61K), and normal human melanocytes (HEMa) were treated with DMSO or palbociclib (1 μM) for 1 day or 8 days. Treated cells were subjected to SA-βgal assay (8 days treatment only) and SA-βgal positive cells were quantified. Data represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). A and RT-qPCR analysis for KGA (B), GAC (C) and GLS2 (D). RT-qPCR data (B–D) were normalized by GAPDH and represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). E 1205Lu and Skmel28 cells treated with DMSO (Control) or palbociclib (1 μM) for 8 days were subjected to western blot for GLS1 and βactin. An arrowhead indicates KGA expression. F 1205Lu cells treated with DMSO (Control) or palbociclib (1 μM) for 1 day or 8 days and 4 clones of 1205Lu palbociclib resistant cells (PR_1, PR_2, PR_3 and PR_4) maintained in the palbociclib-containing medium were harvested and subjected to RT-qPCR analysis for KGA expression. Data were normalized by GAPDH and represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). G 1205Lu, Skmel28 and Skmel2 cells were treated with DMSO or palbociclib for 8 days, and then treated with actinomycin D (0.5 μg/ml) for 2 h. Harvested cells were subjected to RT-qPCR analysis for KGA expression. Data were normalized by GAPDH and represent mean ± SD, p < 0.05 (two-tailed Student’s t-test; n = 3). NS indicates no significance (n = 3).CC BY · PubMed Central
Fig. 2 CB-839 induces senolysis in palbociclib-induced senescent cells. A Scheme for experimental schedule. B WM3918 (BrafWTNrasWT), WM3912 (BrafWTNrasWT), 1205Lu (BrafV600ENrasWT), Skmel28 (BrafV600ENrasWT), Skmel2 (BrafWTNrasQ61R), WM3451 (BrafWTNrasQ61K), HEMa_1 (normal human melanocytes) and HEMa_2 (normal human melanocytes) were treated with DMSO (Control) or palbociclib (1 μM) for 1 day or 8 days followed by CB-839 (50 μM) for an additional 3 days. Harvested cells were subjected to Annexin V staining and analyzed by flow cytometry. Data represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3), NS indicates non-significant (n = 3). C 1205Lu cells treated with DMSO (Control) or palbociclib (1 μM) for 1 day or 8 days followed by CB-839 (50 μM) for an additional 3 days were subjected to SA-βgal assay. D Quantification of SA-βgal positive cells from (C) was shown; data represent mean ± SD. E Skmel28 cells were treated with DMSO (Control), palbociclib (0.25 μM) for 8 days, CB-839 (50 μM) for 3 days, or palbociclib (0.25 μM) for 8 days followed by CB-839 (50 μM) for an additional 3 days. Colony outgrowth was stained with crystal violet after culturing cells for 35 days, including the treatment period. The numbers represent mean ± SD (n = 4).
Fig. 2 CB-839 induces senolysis in palbociclib-induced senescent cells. A Scheme for experimental schedule. B WM3918 (BrafWTNrasWT), WM3912 (BrafWTNrasWT), 1205Lu (BrafV600ENrasWT), Skmel28 (BrafV600ENrasWT), Skmel2 (BrafWTNrasQ61R), WM3451 (BrafWTNrasQ61K), HEMa_1 (normal human melanocytes) and HEMa_2 (normal human melanocytes) were treated with DMSO (Control) or palbociclib (1 μM) for 1 day or 8 days followed by CB-839 (50 μM) for an additional 3 days. Harvested cells were subjected to Annexin V staining and analyzed by flow cytometry. Data represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3), NS indicates non-significant (n = 3). C 1205Lu cells treated with DMSO (Control) or palbociclib (1 μM) for 1 day or 8 days followed by CB-839 (50 μM) for an additional 3 days were subjected to SA-βgal assay. D Quantification of SA-βgal positive cells from (C) was shown; data represent mean ± SD. E Skmel28 cells were treated with DMSO (Control), palbociclib (0.25 μM) for 8 days, CB-839 (50 μM) for 3 days, or palbociclib (0.25 μM) for 8 days followed by CB-839 (50 μM) for an additional 3 days. Colony outgrowth was stained with crystal violet after culturing cells for 35 days, including the treatment period. The numbers represent mean ± SD (n = 4).CC BY · PubMed Central
Fig. 3 Knockdown of GLS1 induces senolysis in palbociclib-induced senescent BrafV600E melanoma cells. A 1205Lu and Skmel28 cell lines, transduced to stably express inducible short hairpin RNAs targeting KGA (shKGA_1 and shKGA_2), were treated with or without doxycycline (100 ng/ml) for 5 days and subjected to western blot for GLS1 and βactin. Arrowheads indicate KGA expression. B 1205Lu and Skmel28 cells from (A) were treated with DMSO (Control), palbociclib (1 μM) for 13 days, or palbociclib (1 μM) for 8 days followed by doxycyclin for an additional 5 days. Harvested cells were subjected to Annexin V staining and analyzed by flow cytometry. Data represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). C 1205Lu and Skmel28 cells introduced with overexpression of KGA were subjected to western blot for GLS1 and βactin. An arrowhead indicates KGA expression. D 1205Lu and Skmel28 cells introduced with or without overexpression of KGA were treated with DMSO (Control) or palbociclib (1 μM) for 8 days. Treated cells were subjected to SA-βgal assay and SA-βgal positive cells were quantified. Data represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). E 1205Lu and Skmel28 cells introduced with overexpression of KGA were treated with DMSO (Control) or palbociclib (1 μM) for 8 days followed by CB-839 (50 μM) for an additional 3 days. Harvested cells were subjected to Annexin V staining and analyzed by flow cytometry. Data represent mean ± SD, NS indicates non-significant (n = 3).
Fig. 3 Knockdown of GLS1 induces senolysis in palbociclib-induced senescent BrafV600E melanoma cells. A 1205Lu and Skmel28 cell lines, transduced to stably express inducible short hairpin RNAs targeting KGA (shKGA_1 and shKGA_2), were treated with or without doxycycline (100 ng/ml) for 5 days and subjected to western blot for GLS1 and βactin. Arrowheads indicate KGA expression. B 1205Lu and Skmel28 cells from (A) were treated with DMSO (Control), palbociclib (1 μM) for 13 days, or palbociclib (1 μM) for 8 days followed by doxycyclin for an additional 5 days. Harvested cells were subjected to Annexin V staining and analyzed by flow cytometry. Data represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). C 1205Lu and Skmel28 cells introduced with overexpression of KGA were subjected to western blot for GLS1 and βactin. An arrowhead indicates KGA expression. D 1205Lu and Skmel28 cells introduced with or without overexpression of KGA were treated with DMSO (Control) or palbociclib (1 μM) for 8 days. Treated cells were subjected to SA-βgal assay and SA-βgal positive cells were quantified. Data represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). E 1205Lu and Skmel28 cells introduced with overexpression of KGA were treated with DMSO (Control) or palbociclib (1 μM) for 8 days followed by CB-839 (50 μM) for an additional 3 days. Harvested cells were subjected to Annexin V staining and analyzed by flow cytometry. Data represent mean ± SD, NS indicates non-significant (n = 3).CC BY · PubMed Central
Fig. 4 CDK4/6i and GLS1i induces senolysis in vemurafenib-resistant melanoma cells. A Vemurafenib-resistant cells derived from 1205Lu and 983B (1205Lu_VR and 983B_VR) treated with DMSO or palbociclib (1 μM) for 1 day or 8 days were subjected to RT-qPCR analysis for KGA expression. Data were normalized by GAPDH and represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). B 1205Lu_VR and 983_VR cells treated with DMSO (Control) or palbociclib (1 μM) for 8 days were subjected to western blot for GLS1 and βactin. C 1205Lu_VR and 983B_VR cells were treated with DMSO (Control) or palbociclib (1 μM) for 1 day or 8 days followed by CB-839 (50 μM) for an additional 3 days. Harvested cells were subjected to Annexin V staining and analyzed by flow cytometry. Data represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). D 1205Lu_VR and 983B_VR cells were treated with palbociclib (1 μM) for 8 days and then cultured in a medium with or without glutamine for an additional 3 days. Harvested cells were subjected to Annexin V staining and analyzed by flow cytometry. Data represent mean ± SD, NS indicates non-significant (n = 3).
Fig. 4 CDK4/6i and GLS1i induces senolysis in vemurafenib-resistant melanoma cells. A Vemurafenib-resistant cells derived from 1205Lu and 983B (1205Lu_VR and 983B_VR) treated with DMSO or palbociclib (1 μM) for 1 day or 8 days were subjected to RT-qPCR analysis for KGA expression. Data were normalized by GAPDH and represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). B 1205Lu_VR and 983_VR cells treated with DMSO (Control) or palbociclib (1 μM) for 8 days were subjected to western blot for GLS1 and βactin. C 1205Lu_VR and 983B_VR cells were treated with DMSO (Control) or palbociclib (1 μM) for 1 day or 8 days followed by CB-839 (50 μM) for an additional 3 days. Harvested cells were subjected to Annexin V staining and analyzed by flow cytometry. Data represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). D 1205Lu_VR and 983B_VR cells were treated with palbociclib (1 μM) for 8 days and then cultured in a medium with or without glutamine for an additional 3 days. Harvested cells were subjected to Annexin V staining and analyzed by flow cytometry. Data represent mean ± SD, NS indicates non-significant (n = 3).CC BY · PubMed Central
Fig. 5 CDK4/6i and GLS1i induces senolysis in vivo. A A total of 1 × 106 cells of 1205Lu_VR cells were subcutaneously injected into 6-week-old SCID mice. Tumor-inoculated mice were treated with palbociclib (90 mg/kg) by oral gavage or CB-839 (200 mg/kg) by oral gavage after tumors reached 5 mm in diameter. After 8 days, a combination of palbociclib (90 mg/kg) and CB-839 (200 mg/kg) was given by oral gavage for an additional 9 days. In each group, comprising 10 tumors, tumor volumes were measured every 2 days. Data represent means ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 10). B Representative images of H&E staining for harvested tumors from (A). The scale bar indicates 50 μm. C The number of mitotic cells was enumerated within a representative 1 mm2 area in each image. Data represent median and interquartile range (IQR), *p < 0.05 (two-tailed Student’s t-test; n = 10). D The proportion of necrotic cells was quantified in each H&E-stained image. Data represent median and interquartile range (IQR), *p < 0.05 (two-tailed Student’s t-test; n = 10). NS indicates non-significant (n = 10). E Representative images of SA-βgal staining and IHC staining for GLS1 and cleaved Caspase-3 in the tumors from (A). The numbers indicate H scores by IHC scoring (see Materials and Methods) from 10 tumors. The scale bar indicates 50 μm. The red arrow indicates Cleaved Caspase-3 positive cells.
Fig. 5 CDK4/6i and GLS1i induces senolysis in vivo. A A total of 1 × 106 cells of 1205Lu_VR cells were subcutaneously injected into 6-week-old SCID mice. Tumor-inoculated mice were treated with palbociclib (90 mg/kg) by oral gavage or CB-839 (200 mg/kg) by oral gavage after tumors reached 5 mm in diameter. After 8 days, a combination of palbociclib (90 mg/kg) and CB-839 (200 mg/kg) was given by oral gavage for an additional 9 days. In each group, comprising 10 tumors, tumor volumes were measured every 2 days. Data represent means ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 10). B Representative images of H&E staining for harvested tumors from (A). The scale bar indicates 50 μm. C The number of mitotic cells was enumerated within a representative 1 mm2 area in each image. Data represent median and interquartile range (IQR), *p < 0.05 (two-tailed Student’s t-test; n = 10). D The proportion of necrotic cells was quantified in each H&E-stained image. Data represent median and interquartile range (IQR), *p < 0.05 (two-tailed Student’s t-test; n = 10). NS indicates non-significant (n = 10). E Representative images of SA-βgal staining and IHC staining for GLS1 and cleaved Caspase-3 in the tumors from (A). The numbers indicate H scores by IHC scoring (see Materials and Methods) from 10 tumors. The scale bar indicates 50 μm. The red arrow indicates Cleaved Caspase-3 positive cells.CC BY · PubMed Central
Fig. 6 GLS1i induces senolysis in vemurafenib-induced senescent cells. 1205Lu cells treated with DMSO (Control) or vemurafenib (0.5 μM) for 8 days were subjected to SA-βgal assay (A) and RT-qPCR analysis for KGA expression (B). RT-qPCR data (B) were normalized by GAPDH and represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). C 1205Lu cells treated with DMSO (Control) or vemurafenib (0.5 μM) for 8 days were subjected to western blot for p-ERK, total ERK, p-S6, total S6 and βactin. D 1205Lu cells were treated with DMSO (Control) or vemurafenib (0.5 μM) for 8 days followed by CB-839 (50 μM) for an additional 3 days. Harvested cells were subjected to Annexin V staining and analyzed by flow cytometer. Data represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3).
Fig. 6 GLS1i induces senolysis in vemurafenib-induced senescent cells. 1205Lu cells treated with DMSO (Control) or vemurafenib (0.5 μM) for 8 days were subjected to SA-βgal assay (A) and RT-qPCR analysis for KGA expression (B). RT-qPCR data (B) were normalized by GAPDH and represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3). C 1205Lu cells treated with DMSO (Control) or vemurafenib (0.5 μM) for 8 days were subjected to western blot for p-ERK, total ERK, p-S6, total S6 and βactin. D 1205Lu cells were treated with DMSO (Control) or vemurafenib (0.5 μM) for 8 days followed by CB-839 (50 μM) for an additional 3 days. Harvested cells were subjected to Annexin V staining and analyzed by flow cytometer. Data represent mean ± SD, *p < 0.05 (two-tailed Student’s t-test; n = 3).CC BY · PubMed Central

Verification

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.

A few free checks a day · papers already verified open instantly · results are public

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 13 references

Research works printed but not linked: 44

  1. McHugh D, Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J Cell Biol. 2018;217:65–77. · DOI · Paper page
  2. Kumari R, Jat P. Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Front Cell Dev Biol. 2021;9:645593. · DOI · Paper page
  3. Ruhland MK, Loza AJ, Capietto A-H, Luo X, Knolhoff BL, Flanagan KC, et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat Commun. 2016;7:11762. · DOI · Paper page
  4. Mavrogonatou E, Pratsinis H, Kletsas D. The role of senescence in cancer development. Semin Cancer Biol. 2020;62:182–91. · DOI
  5. Saleh T, Bloukh S, Carpenter VJ, Alwohoush E, Bakeer J, Darwish S, et al. Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy. Cancers. 2020;12:822. · DOI
  6. Krtolica A, Parrinello S, Lockett S, Desprez P-Y, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging. Proc Natl Acad Sci. 2001;98:12072–7. · DOI · Paper page
  7. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature. 2004;432:332–7. · DOI
  8. Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer. Nat Rev Cancer. 2022;22:340–55. · DOI · Paper page
  9. Bousset L, Gil J. Targeting senescence as an anticancer therapy. Mol Oncol. 2022;16:3855–80. · DOI
  10. Short S, Fielder E, Miwa S, von Zglinicki T. Senolytics and senostatics as adjuvant tumour therapy. EBioMedicine. 2019;41:683–92. · DOI
  11. Prasanna PG, Citrin DE, Hildesheim J, Ahmed MM, Venkatachalam S, Riscuta G, et al. Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy. J Natl Cancer Inst. 2021;113:1285–98. · DOI
  12. van Not OJ, van den Eertwegh AJM, Haanen JB, Blank CU, Aarts MJB, van Breeschoten J, et al. Improving survival in advanced melanoma patients: a trend analysis from 2013 to 2021. EClinicalMedicine. 2024;69:102485. · DOI
  13. Michielin O, Atkins MB, Koon HB, Dummer R, Ascierto PA. Evolving impact of long-term survival results on metastatic melanoma treatment. J Immunother Cancer. 2020;8:e000948. · DOI
  14. Lamba N, Ott PA, Iorgulescu JB. Use of First-Line Immune Checkpoint Inhibitors and Association With Overall Survival Among Patients With Metastatic Melanoma in the Anti-PD-1 Era. JAMA Netw Open. 2022;5:e2225459. · DOI
  15. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66. · DOI · Paper page
  16. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–12. · DOI · Paper page
  17. Yoshida A, Bu Y, Qie S, Wrangle J, Camp ER, Hazard ES, et al. SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors. Sci Adv. 2019;5:eaax6352. · DOI
  18. Yoshida A, Lee EK, Diehl JA. Induction of Therapeutic Senescence in Vemurafenib-Resistant Melanoma by Extended Inhibition of CDK4/6. Cancer Res. 2016;76:2990–3002. · DOI · Paper page
  19. Yoshida A, Diehl JA. CDK4/6 inhibitor: from quiescence to senescence. Oncoscience. 2015;2:896–7. · DOI
  20. Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16:619–34. · DOI · Paper page
  21. Qie S, Yoshida A, Parnham S, Oleinik N, Beeson GC, Beeson CC, et al. Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma. Nat Commun. 2019;10:1296. · DOI
  22. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA. 2008;105:18782–7. · DOI · Paper page
  23. Altman BJ, Hsieh AL, Sengupta A, Krishnanaiah SY, Stine ZE, Walton ZE, et al. MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells. Cell Metab. 2015;22:1009–19. · DOI
  24. Franco J, Balaji U, Freinkman E, Witkiewicz AK, Knudsen ES. Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities. Cell Rep. 2016;14:979–90. · DOI · Paper page
  25. Santiappillai NT, Abuhammad S, Slater A, Kirby L, McArthur GA, Sheppard KE, et al. CDK4/6 Inhibition Reprograms Mitochondrial Metabolism in BRAFV600 Melanoma via a p53 Dependent Pathway. Cancers. 2021;13:524. · DOI
  26. Johmura Y, Yamanaka T, Omori S, Wang TW, Sugiura Y, Matsumoto M, et al. Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science. 2021;371:265–70. · DOI · Paper page
  27. Katt WP, Lukey MJ, Cerione RA. A tale of two glutaminases: homologous enzymes with distinct roles in tumorigenesis. Future Med Chem. 2017;9:223–43. · DOI
  28. Anders L, Ke N, Hydbring P, Choi YJ, Widlund HR, Chick JM, et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer cell. 2011;20:620–34. · DOI · Paper page
  29. Ibrahim H, Lee YJ, Curthoys NP. Renal response to metabolic acidosis: role of mRNA stabilization. Kidney Int. 2008;73:11–8. · DOI
  30. Ince-Dunn G, Okano HJ, Jensen KB, Park WY, Zhong R, Ule J, et al. Neuronal Elav-like (Hu) proteins regulate RNA splicing and abundance to control glutamate levels and neuronal excitability. Neuron. 2012;75:1067–80. · DOI · Paper page
  31. Schroeder JM, Ibrahim H, Taylor L, Curthoys NP. Role of deadenylation and AUF1 binding in the pH-responsive stabilization of glutaminase mRNA. Am J Physiol Ren Physiol. 2006;290:F733–40. · DOI
  32. Sullivan RJ, Flaherty KT. Resistance to BRAF-targeted therapy in melanoma. Eur J Cancer. 2013;49:1297–304. · DOI
  33. Haferkamp S, Borst A, Adam C, Becker TM, Motschenbacher S, Windhövel S, et al. Vemurafenib Induces Senescence Features in Melanoma Cells. J Investigative Dermatol. 2013;133:1601–9. · DOI
  34. Ascenção CFR, Nagampalli RSK, Islam Z, Pinheiro MP, Menezes dos Reis L, Pauletti BA, et al. N-terminal phosphorylation of glutaminase C decreases its enzymatic activity and cancer cell migration. Biochimie. 2018;154:69–76. · DOI
  35. Han T, Zhan W, Gan M, Liu F, Yu B, Chin YE, et al. Phosphorylation of glutaminase by PKCϵ is essential for its enzymatic activity and critically contributes to tumorigenesis. Cell Res. 2018;28:655–69. · DOI
  36. Roberts A, Gandhi L, O’Connor OA, Rudin CM, Khaira D, Xiong H, et al. Reduction in platelet counts as a mechanistic biomarker and guide for adaptive dose-escalation in phase I studies of the Bcl-2 family inhibitor ABT-263. J Clin Oncol. 2008;26:3542. · DOI
  37. Willobee BA, Gaidarski AA, Dosch AR, Castellanos JA, Dai X, Mehra S, et al. Combined Blockade of MEK and CDK4/6 Pathways Induces Senescence to Improve Survival in Pancreatic Ductal Adenocarcinoma. Mol cancer therapeutics. 2021;20:1246–56. · DOI
  38. Ruscetti M, Leibold J, Bott MJ, Fennell M, Kulick A, Salgado NR, et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science. 2018;362:1416–22. · DOI · Paper page
  39. Nassar KW, Hintzsche JD, Bagby SM, Espinoza V, Langouët-Astrié C, Amato CM, et al. Targeting CDK4/6 Represents a Therapeutic Vulnerability in Acquired BRAF/MEK Inhibitor-Resistant Melanoma. Mol cancer therapeutics. 2021;20:2049–60. · DOI
  40. Lelliott EJ, Mangiola S, Ramsbottom KM, Zethoven M, Lim L, Lau PKH, et al. Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma. Cancer Immunol Res. 2021;9:136–46. · DOI
  41. Martin CA, Cullinane C, Kirby L, Abuhammad S, Lelliott EJ, Waldeck K, et al. Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance. Int J cancer. 2018;142:2139–52. · DOI
  42. Zhao Y, Feng X, Chen Y, Selfridge JE, Gorityala S, Du Z, et al. 5-Fluorouracil Enhances the Antitumor Activity of the Glutaminase Inhibitor CB-839 against PIK3CA-Mutant Colorectal Cancers. Cancer Res. 2020;80:4815–27. · DOI
  43. Thompson RM, Dytfeld D, Reyes L, Robinson RM, Smith B, Manevich Y, et al. Glutaminase inhibitor CB-839 synergizes with carfilzomib in resistant multiple myeloma cells. Oncotarget. 2017;8:35863–76. · DOI
  44. Altieri P, Murialdo R, Barisione C, Lazzarini E, Garibaldi S, Fabbi P, et al. 5-fluorouracil causes endothelial cell senescence: potential protective role of glucagon-like peptide 1. Br J Pharmacol. 2017;174:3713–26. · DOI

Cited by

Sorted by citations

Metadata

Authors
Kim, J., Brunetti, B., Kumar, A., Mangla, A., Honda, K., & Yoshida, A.
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2024-12-18
Volume
15
Issue
12
ISSN
2041-4889
DOI
10.1038/s41419-024-07284-3
PMC
PMC11655860
Cited by
16
References
13
Language
en
Licence

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