title: Rapamycin-enhanced mitomycin C-induced apoptotic death is mediated through the S6K1-Bad-Bak pathway in peritoneal carcinomatosis.
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.
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, School of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: X
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, School of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: A-K
authors.initials: AK
authors.lastname: Dilly
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, School of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, School of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Choudry
authors.affiliation: 1] Department of Surgery, University of Pittsburgh Cancer Institute, School of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA [2] Department of Pharmacology & Chemical Biology, University of Pittsburgh Cancer Institute, School of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000819:agonists / Q000494:pharmacology*; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000556:secondary; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000819:agonists / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; C494819:BAD protein, human; C494772:BAK1 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051025:bcl-Associated Death Protein; D016685:Mitomycin; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D020123:Sirolimus