Histone deacetylase inhibitors VPA and TSA induce apoptosis and autophagy in pancreatic cancer cells
Author(s)
Date Issued
2017
Type
article
Volume
40
Issue
40
Start Page
167
End Page
180
ISSN
22113428
Journal
Abstract
Histone deacetylase inhibitors (HDACis) are antineoplastic agents that affect cell growth, differentiation and invasion in a variety of different cancer types, although the underlying mechanisms have not been completely clarified yet. In this study, we compared the effects of two HDACis, namely Trichostatin A (TSA) and Valproic Acid (VPA) in the induction of both cell death and autophagy in the pancreatic cancer cell lines PaCa44 and Panc1. These cells are characterized by a high metastatic capacity and display k-RAS/p53 double mutation. We found that both HDACis reduced cell survival and induced pancreatic cancer cells apoptosis by triggering mitochondrial membrane depolarization, cytochrome C release and caspase 3 activation, although VPA was more effective than TSA, especially in Panc1. Among the underlying molecular mechanism/s leading to the HDACis-mediated cytotoxic effect, we found that ERK1/2 was de-phosphorylated and c-Myc and mutant p53 protein levels were reduced by VPA and to a lesser extent by TSA. Up-regulation of p21 and Puma was also observed, suggesting a possible wild-type p53 re-activation, concomitantly with mutant p53 degradation. In addition, in both cell lines VPA increased the pro-apoptotic Bim, reduced the anti-apoptotic Mcl-1, induced ROS production and autophagy while TSA was able to mediate these effects only in PaCA44 cells. These results suggest that VPA, that specifically inhibits class I HDAC, may have a stronger and broader cytotoxic effect in comparison with TSA against pancreatic cancer and could represent a better choice in pancreatic anticancer therapy, alone or in combination with other drugs.
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Checksum (MD5)
8989e76bed25a9b111834232a930d187
Conference(s)
CELLULAIR ONCOLOGY