TrichostatinA induces bladder cancer cell death via intrinsic apoptosis at the earlyphase and Sp1‑survivin downregulation at the latephase of treatment.

Abstract

Histone deacetylase (HDAC) inhibitors have been widely shown to result in cancer cell death. The present study investigated the mechanisms underlying the antitumor effects of the phytochemical trichostatinA (TSA), a classic pan-HDAC inhibitor, in 5,637 urinary bladder cancer cells. It was found that TSA caused cell cycle arrest at the G2/M and G1phase accompanied by reduced expression of cyclinD1 and upregulated induction of p21. In addition, TSA induced morphological changes, reduced cell viability and apoptotic cell death in 5,637cells through caspase-3 activation followed by PARP cleavage. The loss of mitochondrial membrane potential (MMP) indicated that TSA induced apoptosis in 5,637cells through the intrinsic mitochondrial pathway. TSA significantly suppressed Akt activity at 12h after treatment, suggesting that the apoptosis in the early phase was mediated by Akt inhibition. In addition, the protein level of transcription factor Sp1 was decreased at 24h after TSA treatment, which likely led to the downregulation of survivin gene expression, and then contributed to the antitumor activity of TSA. Taken together, the present study delineated that TSA-induced growth inhibition and apoptosis in 5,637cells was associated with pAKT inhibition and MMP loss at the early phase, followed by downregulation of Sp1 and survivin at the late phase of treatment.