Inhibition of androgen-regulated TMPRSS2 and lipogenic enzymes in prostate and lung carcinoma cell lines by a cisplatin prodrug

ABSTRACT

The main causative agent for the global pandemic of COVID-19 is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Developing therapeutic strategies to stop the virus is the hour of need. According to the recent clinical reports, it is seen that an androgen-regulated host cell serine protease TMPRSS2 acts on the spike protein of the SARS-CoV-2 virus which interacts with the host angiotensin-converting enzyme 2 (ACE2) and enters the host cell to cause the infection. Reports also suggest that TMPRSS2 is regulated by androgen present in prostate cells and it is highly expressed in PCa patients. Our lab has recently synthesized a new cisplatin prodrug which is a conjugate of lauric acid and cisplatin that potentially works very effectively in various androgen dependent and independent prostate cancer (PCa) cells. The cisplatin prodrug unlike other conventional platinum drugs is involved in inhibition of one of the major metabolic pathways of the PCa cells. Preliminary results show that, the prodrug in combination with the anti-androgen bicalutamide has an increased inhibition on the expression of TMPRSS2 in androgen dependent PCa and lung carcinoma cells along with down-regulation of some the lipogenic enzymes in-vitro. Here, we propose that the prodrug inhibits one of the mitochondrial metabolic pathways making the PCa cells sensitive towards cisplatin-based chemotherapy along with reducing the expression of TMPRSS2. Once completed, our work will provide an inside story of cisplatin prodrug mediated alteration of lipogenesis of cells in PCa tumor microenvironment resulting in a platform that has the potential to reduce the burden of cancer aggressiveness in both androgen dependent and independent PCa and also can be used as a potent chemotherapeutic agent against COVID-19.