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

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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.

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Acknowledgments

Part of this work was performed at the Department of Chemistry and Biochemistry, Northern Illinois University, Faraday Hall, DeKalb, IL 60115, and the Department of Biomedical Sciences, Ohio University, Athens, OH 45701, USA. RNB gratefully acknowledges the partial support of this work by the Cancer Prevention Research Institute of Texas (Grant No. RP130553).

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Authors and Affiliations

  1. Department of Chemistry, Kansas State University, Manhattan, KS, 66506, USA

    L. Maurmann

  2. Department of Biology and Biochemistry, University of Houston, Houston, TX, 77204, USA

    L. Belkacemi, S. Moghaddas & R. N. Bose

  3. Baylor College of Medicine, Houston, TX, 77030, USA

    N. R. Adams

  4. Temple University, The Office of Technology Development and Commercialization, Philadelphia, PA, 19122, USA

    P. M. Majmudar

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  1. L. Maurmann
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  2. L. Belkacemi
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Correspondence to L. Belkacemi or R. N. Bose.

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Maurmann, L., Belkacemi, L., Adams, N.R. et al. A novel cisplatin mediated apoptosis pathway is associated with acid sphingomyelinase and FAS proapoptotic protein activation in ovarian cancer. Apoptosis 20, 960–974 (2015). https://doi.org/10.1007/s10495-015-1124-2

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