Prostate cancer is a multistep molecular disorder that arises because of a miscellany of proteins. Calcium channels, hotspots in genome and susceptibility to DNA damage, an illegitimate repair of the genome, all these factors work synchronously at various levels to worsen the clinical management of the disease. Fusion transcripts are recently acclaimed candidates for exacerbation of the disease. Erlotinib has been used for the treatment of various molecular pathologies but it has been ineffective in producing desired level of effects. It is therefore used in conjunction with other therapeutic intercessions. Despite the characterization of a number of fusion genes, therapeutic interventions to address the underlying mechanisms are still insufficient. In this particular study, we have applied a combinatorial approach to silence some calcium channels which have been documented earlier to be contributory in disease progression. The siRNA against TRPM2, TRPV6 and TRPC6 were used to evaluate the striking synergy. Simultaneously, the effects were evaluated for ATM activation and a downregulation of the chimeric gene. The expression of channels was blocked effectively as analyzed by RT PCR and Blotting assays. TRPM2 ablation instigated a DNA damage response which was observed by the blotting assay for phosphorylated ATM. Dampening the expression of TRPV6 and TRPC6 by siRNA concomitantly inhibited the genomic rearrangements. We have evaluated the synergistic impact of Erlotinib along with TRP interference on genomic instability. The observations are indicative of the fact that, silencing of calcium channels offer exciting avenues for getting a step closer to personalized medicine.
Key words: ATM, TMPRSS2-ERG, TRPM2, TRPV6, TRPC6, genomic instability, prostate cancer.
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