LDH inhibition impacts on heat shock response and induces senescence of hepatocellular carcinoma cells

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Marcella ManerbaGiuseppina Di Stefano

Abstract

In normal cells, heat shock response (HSR) is rapidly induced in response to a variety of harmful conditions and represents one of the most efficient defense mechanism. In cancer tissues, constitutive activation converts HSR into a life-threatening process, which plays a major role in helping cell survival and proliferation. Overexpression of heat shock proteins (HSPs) has been widely reported in human cancers and was found to correlate with tumor progression. Hepatocellular carcinoma is one of the conditions in which HSR activation was shown to have the highest clinical significance. Transcription of HSPs is induced by HSF-1, which also activates glycolytic metabolism and increases the expression of LDH-A, the master regulator of the Warburg effect. In this paper, we tried to explore the relationship between HSR and LDH-A. In cultured hepatocellular carcinoma cells, by using two enzyme inhibitors (oxamate and galloflavin), we found that the reduction of LDH-A activity led to decreased level and function of the major HSPs involved in tumorigenesis. Galloflavin (a polyphenol) also inhibited the ATPase activity of two of the examined HSPs. Finally, hindering HSR markedly lowered the alpha-fetoprotein cellular levels and induced s...Continue Reading

Citations

Feb 18, 2020·Future Medicinal Chemistry·Mark R WoodfordMehdi Mollapour
Nov 19, 2019·Frontiers in Oncology·Karen G de la Cruz-LópezJoaquín Manzo-Merino
Aug 10, 2021·Frontiers in Oncology·Kevin X LiuMichael G Milligan
Sep 24, 2021·Cancer Control : Journal of the Moffitt Cancer Center·Karolina KozalAnna Krześlak

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