Down regulation of lactate dehydrogenase initiates apoptosis in HeLa and MCF-7 cancer cells through increased voltage-dependent anion channel protein and inhibition of BCL2.

Suhail Al-Salam,Karthishwaran Kandhan,Manjusha Sudhadevi

doi:10.18632/oncotarget.27950

Suhail Al-Salam, Karthishwaran Kandhan + Show 1 more

Open Access

https://doi.org/10.18632/oncotarget.27950

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Journal: Oncotarget	Publication Date: Apr 27, 2021
Citations: 3	License type: cc-by

Affiliation: United Arab Emirates University

Abstract

Malignant cells commonly use aerobic glycolysis for ATP production; this is known as the Warburg effect, where pyruvate is converted to lactate, by enzyme lactate dehydrogenase A (LDH-A). In this study, we have investigated the effect of inhibition of LDH-A on cells viability and identifying the mechanism of cell death in HeLa and MCF-7 cancer cells.Human cervical cancer HeLa cell line and breast cancer MCF-7 cell line were used to investigate the effect of inhibition of LDH-A by sodium oxamate on cell survival and proliferation using western blot, spectrophotometry, and immunofluorescent study.There was significant reduction in LDH-A (P < 0.001) and cell viability (P < 0.001) in a dose-dependent mode in both HeLa and MCF-7 SO-treated cancer cells. The voltage-dependent anion channel (VDAC) protein was significantly increased (P < 0.001) in association with decreased LDH-A. The proapoptotic proteins; cytochrome C (P < 0.001), BAX (P < 0.001), cleaved caspase-3 (P < 0.001), cleaved caspase-8 (P < 0.001), and cleaved caspase-9 (P < 0.001) were significantly increased in association with decreased LDH-A. While, the anti-apoptotic protein Bcl2 was significantly decreased (P < 0.001) in association with decreased LDH-A.We conclude that Inhibition of LDH-A can decrease cells viability through activation of intrinsic apoptotic pathway via increased VDAC protein and inhibition of Bcl2 as well as activation of the extrinsic apoptotic pathway through activation of caspase-8.

Highlights

Malignant cells commonly use aerobic glycolysis for ATP production; this is known as the Warburg effect [1]
We show SO significantly reduces lactate dehydrogenase A (LDH-A) in a dose-dependent mode
We show SO significantly inhibits the viability of human cervical (HeLa) and breast (MCF-7) cancer cells in a dose-dependent fashion

Summary

Introduction

Malignant cells commonly use aerobic glycolysis for ATP production; this is known as the Warburg effect [1]. Pyruvate is converted to lactate by enzyme lactate dehydrogenase A (LDH-A) where nicotinamide adenine dinucleotide (NAD+) is generated from NADH in this process [2]. The production of NAD+ is required by glyceraldehyde 3-phosphate dehydrogenase to maintain glycolysis and ATP production [2]. LDH, which owns two subunits LDH-A and LDH-B, is an enzyme commonly existing in human cells [3]. LDH-A catalyzes the conversion of pyruvate to lactate with the liberation of NAD+, which possesses a vital role in glycolysis. It has long been noted that LDH- A expression is upregulated in human neoplastic tissues [3]

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