Human GM3 Synthase Attenuates Taxol-Triggered Apoptosis Associated with Downregulation of Caspase-3 in Ovarian Cancer Cells

Su Huang, Khadijeh Bijangi-Vishehsaraei, Mohammad Reza Saadatzadeh, Ahmad R. Safa

Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, USA..
Department of Pharmacology and Toxicology, Indiana University Simon Cancer Center, Indianapolis, USA.

DOI: 10.4236/jct.2012.35065                

Abstract

Background: Taxol (paclitaxel) inhibits proliferation and induces apoptosis in a variety of cancer cells, but it also upregulates cytoprotective proteins and/or pathways that compromise its therapeutic efficacy. Materials and Method: The roles of GM3 synthase (α2,3-sialyltransferase, ST3Gal V), in attenuating Taxol-induced apoptosis and triggering drug resistance were determined by cloning and overexpressing this enzyme in SKOV3 human ovarian cancer cell line, treating SKOV3 and the transfectants (SKOV3/GS) with Taxol and determining apoptosis, cell survival, clonogenic ability, and caspase-3 activation. Results: In this report, we demonstrated that Taxol treatment resulted in apoptosis which was associated with caspase-3 activation. Taxol treatment upregulated the expression of human GM3 synthase, an enzyme that transfers a sialic acid to lactosylceramide. Moreover, we cloned the full-length GM3 synthase gene and showed for the first time that forced expression of GM3 synthase attenuated Taxol-induced apoptosis and increased resistance to Taxol in SKOV3 cells. Conclusions: GM3 synthase overexpression inhibited Taxol-triggered caspase-3 activation, revealing that upregulation of GM3 synthase prevents apoptosis and hence reduces the efficacy of Taxol therapy.

Keywords

Ovarian Cancer; Taxol; GM3 Synthase; Apoptosis; Caspase-8; Drug Resistance

Conflicts of Interest

The authors declare no conflicts of interest.

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