A novel cisplatin mediated apoptosis pathway is associated with acid sphingomyelinase and FAS proapoptotic protein activation in ovarian cancer

Apoptosis. 2015 Jul;20(7):960-74. doi: 10.1007/s10495-015-1124-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • CHO Cells
  • Cell Membrane / metabolism
  • Cell Survival / drug effects
  • Cisplatin / pharmacology*
  • Cricetulus
  • Female
  • Humans
  • Ovarian Neoplasms / metabolism*
  • Signal Transduction / drug effects
  • Sphingomyelin Phosphodiesterase / metabolism*
  • fas Receptor / metabolism*


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • fas Receptor
  • acid sphingomyelinase-1
  • Sphingomyelin Phosphodiesterase
  • Cisplatin