title: A novel cisplatin mediated apoptosis pathway is associated with acid sphingomyelinase and FAS proapoptotic protein activation in ovarian cancer.
abstract: Platinum-based anticancer drugs, including cisplatin and carboplatin, have been cornerstones in the treatment of solid tumors. We report here that these DNA-damaging agents, particularly cisplatin, induce apoptosis through plasma membrane disruption, triggering FAS death receptor via mitochondrial (intrinsic) pathways. Our objectives were to: quantify the composition of membrane metabolites; and determine the potential involvement of acid sphingomyelinase (ASMase) in the FAS-mediated apoptosis in ovarian cancer after cisplatin treatment. The resulting analysis revealed enhanced apoptosis as measured by: increased phosphocholine, and glycerophosphocholine; elevated cellular energetics; and phosphocreatine and nucleoside triphosphate concentrations. The plasma membrane alterations were accompanied by increased ASMase activity, leading to the upregulation of FAS, FASL and related pro-apoptotic BAX and PUMA genes. Moreover FAS, FASL, BAX, PUMA, CASPASE-3 and -9 proteins were upregulated. Our findings implicate ASMase activity and the intrinsic pathways in cisplatin-mediated membrane demise, and contribute to our understanding of the mechanisms by which ovarian tumors may become resistant to cisplatin.
authors.affiliation: Department of Chemistry, Kansas State University, Manhattan, KS, 66506, USA.
authors.forename: L
authors.initials: L
authors.lastname: Maurmann
authors.forename: L
authors.initials: L
authors.lastname: Belkacemi
authors.forename: N R
authors.initials: NR
authors.lastname: Adams
authors.forename: P M
authors.initials: PM
authors.lastname: Majmudar
authors.forename: S
authors.initials: S
authors.lastname: Moghaddas
authors.forename: R N
authors.initials: RN
authors.lastname: Bose
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003412:Cricetulus; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D019014:fas Receptor; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D002945:Cisplatin