Abstract
Abstract The progression of human brain, bladder and prostate cancers, considered inflammatory cancers, is characterized by the acquisition of metastatic and drug resistance profiles which remain major impediments to the efficacious delivery of therapeutic intervention. Recent localization and protein interaction studies of the sphingolipid metabolism protein, serine palmitoyltransferase-1, SPTLC1, suggest a signaling, other than metabolic role during cellular response to diverse stress stimuli. The current study examined chemosensitivity to genotoxic compounds by a set of SPTLC1 recombinant cancer cell lines. When exposed to the anti-cancer drugs celecoxib and fenretinide, SPTLC1 localization as determined by confocal immunofluorescence microscopy showed its translocation to focal adhesion sites. This allows for possible interaction and crosstalk with other stress response proteins involved in regulating cell growth, differentiation, proliferation, apoptosis, migration and other processes by which cells respond to stress stimuli. Stress-inducible gene expression profile of cytochrome p450 transcripts shows differential attenuation of the Cyp1A1, 1A2 and 3A4 species. Altered expression of the genes for the cytochrome p450 xenobiotic metabolism proteins can have profound effect on the toxicity of anticancer drugs especially those with narrow therapeutic window. Taken together, the heterologous expression of a C-terminal modified SPTLC1 gene in the human cancer cell lines used in this study was found to mediate an altered drug response profile consistent with acquisition of a multidrug resistance phenotype. This is exemplified in increased resistance to anti-proliferative effect of therapeutic drugs, differential attenuation of transcriptional expression of Cyp450 species, as well as, chemical induced DNA fragmentation. The observations further support a general role for SPTLC1 in cellular stress response and its potential contribution in cellular resistance to cytotoxic drugs.
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