CoChat
Sign Up
Cited by 24PI3K/AKT/mTOR signaling in cancerCell death mechanisms and regulationIntraperitoneal and Appendiceal Malignancies

Rapamycin-enhanced mitomycin C-induced apoptotic death is mediated through the S6K1–Bad–Bak pathway in peritoneal carcinomatosis

Open access
Song, X, Dilly, A-K, Kim, S-Y, Choudry, H A, Lee, Y J·2014·Cell Death & Disease
DOI 10.1038/cddis.2014.242PMC PMC4607229
Open this paper in CoChat — free accountOpen PDF

Abstract

Peritoneal carcinomatosis (PC) is the most common secondary cancerous disease, and more effective novel regimens are needed. In this study, we identified a novel combination treatment for PC, chemotherapeutic agent mitomycin C in combination with mTOR (mammalian target of rapamycin) inhibitor rapamycin. We observed that the combination of mitomycin C and rapamycin induced synergistic cytotoxicity and apoptosis, which was mediated through an increase in caspase activation. The combination of mitomycin C and rapamycin inactivated p70 S6 ribosomal kinase (S6K1) and dephosphorylated Bad, leading to dissociation of Bcl-xL from Bak, which resulted in Bak oligomerization, mitochondria dysfunction and cytochrome c release. PF-4708671, a S6K1-specific inhibitor, enhanced the combination treatment-induced apoptosis, whereas S6K1 E389 DeltaCT-HA (S6K1 active form) dramatically decreased the induction of apoptosis. In addition, the combination treatment significantly inhibited LS174T intraperitoneal tumor growth in vivo. This study provides a preclinical rationale for apoptosis induction linked with the mTOR pathway through a combination of chemotherapeutic agents and mTOR inhibitor, and will support this combinatorial strategy to PC patients.

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/cddis.2014.242

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.

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?

  • A combined MMC-mTOR inhibitor approach produces synergistic effects on apoptosis through the decreased function of the S6K1-BAD-BAK pathway.

    “For that reason, a combined MMC-mTOR inhibitor approach produces synergistic effects on apoptosis through the decreased function of the S6K1–BAD–BAK pathway [27].”

    From Combining Mitomycin C with inhibition of BAD phosphorylation enhances apoptotic cell death in advanced cervical cancer (2024) · cites this paper as [27]

    The Abstract reports synergistic apoptosis from mitomycin C plus the mTOR inhibitor rapamycin through the S6K1–Bad–Bak pathway. But it reports decreased S6K1 activity followed by Bad dephosphorylation and Bak oligomerization, not decreased function of the pathway as a whole. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

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

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

The citation lists haven’t been fetched yet

References 49 · Cited by 24

Research works printed but not linked: 47

  1. 1Seidl C, Essler M. Radioimmunotherapy for peritoneal cancers. Immunotherapy 2013; 5: 395–405. 23557422
  2. 2Knorr C, Reingruber B, Meyer T, Hohenberger W, Stremmel C. Peritoneal carcinomatosis of colorectal cancer: incidence, prognosis, and treatment modalities. Int J Colorectal Dis 2004; 19: 181–187. 12955416
  3. 3Ceelen WP. Current management of peritoneal carcinomatosis from colorectal cancer. Minerva Chir 2013; 68: 77–86. 23584267
  4. 4Pirnia F, Schneider E, Betticher DC, Borner MM. Mitomycin C induces apoptosis and caspase-8 and -9 processing through a caspase-3 and Fas-independent pathway. Cell Death Differ 2002; 9: 905–914. 12181741
  5. 5Wu KY, Wang HZ, Hong SJ. Mechanism of mitomycin-induced apoptosis in cultured corneal endothelial cells. Mol Vis 2008; 14: 1705–1712. 18806879 PMC2538491
  6. 6Van der Speeten K, Stuart OA, Chang D, Mahteme H, Sugarbaker PH. Changes induced by surgical and clinical factors in the pharmacology of intraperitoneal mitomycin C in 145 patients with peritoneal carcinomatosis. Cancer Chemother Pharmacol 2011; 68: 147–156. 20857115
  7. 7Cohen MS, Al-Kasspooles MF, Williamson SK, Henry D, Broward M, Roby KF. Combination intraperitoneal chemotherapy is superior to mitomycin C or oxaliplatin for colorectal carcinomatosis in vivo. Ann Surg Oncol 2010; 17: 296–303. 19707832
  8. 8Kornek GV, Schuell B, Laengle F, Gruenberger T, Penz M, Karall K et al. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol 2004; 15: 478–483. 14998852
  9. 9Saif MW, Kaley K, Brennan M, Garcon MC, Rodriguez G. Mitomycin-C and capecitabine (MIXE) as salvage treatment in patients with refractory metastatic colorectal cancer: a retrospective study. Anticancer Res 2013; 33: 2743–2746. 23749935
  10. 10Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med 2005; 11: 353–361. 16002336
  11. 11Tee AR, Proud CG. Staurosporine inhibits phosphorylation of translational regulators linked to mTOR. Cell Death Differ 2001; 8: 841–849. 11526437
  12. 12Tee AR, Proud CG. DNA-damaging agents cause inactivation of translational regulators linked to mTOR signalling. Oncogene 2000; 19: 3021–3031. 10871854
  13. 13Ramanathan A, Schreiber SL. Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci USA 2009; 106: 22229–22232. 20080789 PMC2796909
  14. 14Choo AY, Yoon SO, Kim SG, Roux PP, Blenis J. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc Natl Acad Sci USA 2008; 105: 17414–17419. 18955708 PMC2582304
  15. 15Fasolo A, Sessa C. mTOR inhibitors in the treatment of cancer. Expert Opin Investig Drugs 2008; 17: 1717–1734. 18922108
  16. 16Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006; 5: 671–688. 16883305
  17. 17Dhanasekaran DN, Reddy EP. JNK signaling in apoptosis. Oncogene 2008; 27: 6245–6251. 18931691 PMC3063296
  18. 18Tandon P, Gallo CA, Khatri S, Barger JF, Yepiskoposyan H, Plas DR. Requirement for ribosomal protein S6 kinase 1 to mediate glycolysis and apoptosis resistance induced by Pten deficiency. Proc Natl Acad Sci USA 2011; 108: 2361–2365. 21262837 PMC3038712
  19. 19Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 1997; 275: 661–665. 9005851
  20. 20Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 1998; 10: 262–267. 9561851
  21. 21Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, Wettenhall RE et al. The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. Embo J 1995; 14: 5279–5287. 7489717 PMC394637
  22. 22Danial NN. BAD: undertaker by night, candyman by day. Oncogene 2008; 27(Suppl 1): S53–S70. 19641507
  23. 23Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 1995; 80: 285–291. 7834748
  24. 24Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 2001; 292: 727–730. 11326099 PMC3049805
  25. 25Carethers JM, Pham TT. Mutations of transforming growth factor beta 1 type II receptor, BAX, and insulin-like growth factor II receptor genes in microsatellite unstable cell lines. In Vivo 2000; 14: 13–20. 10757056
  26. 26Pearce LR, Alton GR, Richter DT, Kath JC, Lingardo L, Chapman J et al. Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem J 2010; 431: 245–255. 20704563
  27. 27Dennis PB, Pullen N, Kozma SC, Thomas G. The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases. Mol Cell Biol 1996; 16: 6242–6251. 8887654 PMC231627
  28. 28Schalm SS, Blenis J. Identification of a conserved motif required for mTOR signaling. Curr Biol 2002; 12: 632–639. 11967149
  29. 29Liu M, Howes A, Lesperance J, Stallcup WB, Hauser CA, Kadoya K et al. Antitumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancer. Cancer Res 2005; 65: 5325–5336. 15958580
  30. 30Varghese S, Chen Z, Bartlett DL, Pingpank JF, Libutti SK, Steinberg SM et al. Activation of the phosphoinositide-3-kinase and mammalian target of rapamycin signaling pathways are associated with shortened survival in patients with malignant peritoneal mesothelioma. Cancer 2011; 117: 361–371. 20839315 PMC6993181
  31. 31Wagner OJ, Inglin RA, Bisch-Knaden S, Mettler D, Borner M, Candinas D et al. Sirolimus and intraoperative hyperthermic peritoneal chemoperfusion with mitomycin-C do not impair healing of bowel anastomoses. Transpl Int 2008; 21: 554–563. 18225992
  32. 32Werner D, Atmaca A, Pauligk C, Pustowka A, Jager E, Al-Batran SE. Phase I study of everolimus and mitomycin C for patients with metastatic esophagogastric adenocarcinoma. Cancer Med 2013; 2: 325–333. 23930209 PMC3699844
  33. 33Shang YC, Chong ZZ, Wang S, Maiese K. Prevention of beta-amyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL. Aging (Albany NY) 2012; 4: 187–201. 22388478 PMC3348479
  34. 34Wang Y, Hu Z, Liu Z, Chen R, Peng H, Guo J et al. MTOR inhibition attenuates DNA damage and apoptosis through autophagy-mediated suppression of CREB1. Autophagy 2013; 9: 2069–2086. 24189100
  35. 36Maiese K, Chong ZZ, Shang YC, Wang S. Targeting disease through novel pathways of apoptosis and autophagy. Expert Opin Ther Targets 2012; 16: 1203–1214. 22924465 PMC3500415
  36. 37Shor B, Gibbons JJ, Abraham RT, Yu K. Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle 2009; 8: 3831–3837. 19901542
  37. 38Wang X, Sun SY. Enhancing mTOR-targeted cancer therapy. Expert Opin Ther Targets 2009; 13: 1193–1203. 19694499 PMC2810099
  38. 39Dormond O, Madsen JC, Briscoe DM. The effects of mTOR-Akt interactions on anti-apoptotic signaling in vascular endothelial cells. J Biol Chem 2007; 282: 23679–23686. 17553806 PMC3383050
  39. 40Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ. p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci USA 2001; 98: 9666–9670. 11493700 PMC55509
  40. 41Ismail HM. Overexpression of s6 kinase 1 in brain tumours is associated with induction of hypoxia-responsive genes and predicts patients' survival. J Oncol 2012; 2012: 416927. 22570651 PMC3335255
  41. 42Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y et al. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J 2004; 23: 1889–1899. 15071501 PMC394248
  42. 43Song X, Kim SY, Lee YJ. The role of Bcl-xL in synergistic induction of apoptosis by mapatumumab and oxaliplatin in combination with hyperthermia on human colon cancer. Mol Cancer Res 2012; 10: 1567–1579. 23051936 PMC3528808
  43. 44Taghiyev AF, Guseva NV, Harada H, Knudson CM, Rokhlin OW, Cohen MB. Overexpression of BAD potentiates sensitivity to tumor necrosis factor-related apoptosis-inducing ligand treatment in the prostatic carcinoma cell line LNCaP. Mol Cancer Res 2003; 1: 500–507. 12754297
  44. 45Masters SC, Yang H, Datta SR, Greenberg ME, Fu H. 14-3-3 inhibits Bad-induced cell death through interaction with serine-136. Mol Pharmacol 2001; 60: 1325–1331. 11723239
  45. 46Aluvila S, Mandal T, Hustedt E, Fajer P, Choe JY, Oh KJ. Organization of the mitochondrial apoptotic BAK pore: oligomerization of the BAK homodimers. J Biol Chem 2013; 11: 11. PMC3908389 24337568
  46. 47Marchion DC, Cottrill HM, Xiong Y, Chen N, Bicaku E, Fulp WJ et al. BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival. Clin Cancer Res 2011; 17: 6356–6366. 21849418 PMC3186862
  47. 48Pecot CV, Rupaimoole R, Yang D, Akbani R, Ivan C, Lu C et al. Tumour angiogenesis regulation by the miR-200 family. Nat Commun 2013; 4: 2427. 24018975 PMC3904438

Authors
Song, X., Dilly, A.-K., Kim, S.-Y., Choudry, H. A., & Lee, Y. J.
Affiliations
University of Pittsburgh (US)
Corresponding author
Lee, Y J
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2014-06-05
Volume
5
Issue
6
Pages
e1281-e1281
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/cddis.2014.242
PMC
PMC4607229
OpenAlex
W2034691444
Cited by
24
References
49
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 7 · 2019: 1 · 2018: 3 · 2017: 3 · 2016: 1 · 2015: 1
FWCI
0.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Cancer Institute, University of Pittsburgh (P30CA047904)
  • National Cancer Institute (R01CA140554, CA140554, P30CA047904)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Surgery › Intraperitoneal and Appendiceal Malignancies
Keywords
peritoneal carcinomatosis, rapamycin, mitomycin C, mTOR inhibition, S6K1, Bad, Bak, apoptosis, Bcl-xL, caspase activation, mitochondrial dysfunction, cytochrome c release, combination chemotherapy, LS174T cells, synergistic cytotoxicity
MeSH terms
Adenocarcinoma, Animals, Antibiotics, Antineoplastic, Humans, Mice, Nude, Peritoneal Neoplasms, Mitomycin, Apoptosis, Sirolimus, Ribosomal Protein S6 Kinases, 70-kDa, Cell Line, Tumor, bcl-2 Homologous Antagonist-Killer Protein, bcl-Associated Death Protein, Mice

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