Overexpression of pyruvate dehydrogenase kinase 1 in retinoblastoma: A potential therapeutic opportunity for targeting vitreous seeds and hypoxic regions

PloS One
Swatishree SradhanjaliMamatha M Reddy

Abstract

Pyruvate dehydrogenase kinase 1 (PDK1), a key enzyme implicated in metabolic reprogramming of tumors, is induced in several tumors including glioblastoma, breast cancer and melanoma. However, the role played by PDK1 is not studied in retinoblastoma (RB). In this study, we have evaluated the expression of PDK1 in RB clinical samples, and studied its inhibition as a strategy to decrease cell growth and migration. We show that PDK1 is specifically overexpressed in RB patient samples especially in vitreous seeds and hypoxic regions and cell lines compared to control retina using immunohistochemistry and real-time PCR. Our results further demonstrate that inhibition of PDK1 using small molecule inhibitors dichloroacetic acid (DCA) and dichloroacetophenone (DAP) resulted in reduced cell growth and increased apoptosis. We also confirm that combination treatment of DCA with chemotherapeutic agent carboplatin further enhanced the therapeutic efficacy compared to single drug treatment. In addition, we observed changes in glucose uptake, lactate and reactive oxygen species (ROS) levels as well as decreased cell migration in response to PDK1 inhibition. Additionally, we show that DCA treatment led to inhibition of PI3K/Akt pathway and redu...Continue Reading

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Aug 20, 2018·International Journal of Cancer. Journal International Du Cancer·Tereza GoliasIoanna Papandreou
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Nov 13, 2019·Chemical Communications : Chem Comm·Yiming LiXuefeng Jiang
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May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Naheed Arfin Borah, Mamatha M Reddy
Jun 3, 2021·Metabolites·Benedikt FeuereckerWolfgang Eisenreich

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Methods Mentioned

BETA
PCR
flow cytometry

Software Mentioned

compusyn

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