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Cells
Volume 10
Issue 1
10.3390/cells10010097
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Article

Fer and FerT Govern Mitochondrial Susceptibility to Metformin and Hypoxic Stress in Colon and Lung Carcinoma Cells

by
Odeya Marciano
1,†,
Linoy Mehazri
1,†,
Sally Shpungin
1,
Alexander Varvak
1,
Eldad Zacksenhaus
2 and
Uri Nir
1,*
1
The Mina and Everard Goodman Faculty of Life-Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel
2
Laboratory of Medicine & Pathology, University of Toronto, Toronto, ON M5G 2M1, Canada
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this manuscript.
Cells 2021, 10(1), 97; https://doi.org/10.3390/cells10010097
Received: 25 November 2020 / Revised: 26 December 2020 / Accepted: 5 January 2021 / Published: 7 January 2021
(This article belongs to the Special Issue Mitochondria in Cancer: A Neglected Functional Reprogramming with Fundamental Pathophysiological Implications)
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Abstract

Aerobic glycolysis is an important metabolic adaptation of cancer cells. However, there is growing evidence that reprogrammed mitochondria also play an important metabolic role in metastatic dissemination. Two constituents of the reprogrammed mitochondria of cancer cells are the intracellular tyrosine kinase Fer and its cancer- and sperm-specific variant, FerT. Here, we show that Fer and FerT control mitochondrial susceptibility to therapeutic and hypoxic stress in metastatic colon (SW620) and non-small cell lung cancer (NSCLC-H1299) cells. Fer- and FerT-deficient SW620 and H1299 cells (SW∆Fer/FerT and H∆Fer/FerT cells, respectively) become highly sensitive to metformin treatment and to hypoxia under glucose-restrictive conditions. Metformin impaired mitochondrial functioning that was accompanied by ATP deficiency and robust death in SW∆Fer/FerT and H∆Fer/FerT cells compared to the parental SW620 and H1299 cells. Notably, selective knockout of the fer gene without affecting FerT expression reduced sensitivity to metformin and hypoxia seen in SW∆Fer/FerT cells. Thus, Fer and FerT modulate the mitochondrial susceptibility of metastatic cancer cells to hypoxia and metformin. Targeting Fer/FerT may therefore provide a novel anticancer treatment by efficient, selective, and more versatile disruption of mitochondrial function in malignant cells. View Full-Text
Keywords: Fer; FerT; reprogrammed mitochondria; oxidative phosphorylation; metformin; hypoxia; malignant cells Fer; FerT; reprogrammed mitochondria; oxidative phosphorylation; metformin; hypoxia; malignant cells
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MDPI and ACS Style

Marciano, O.; Mehazri, L.; Shpungin, S.; Varvak, A.; Zacksenhaus, E.; Nir, U. Fer and FerT Govern Mitochondrial Susceptibility to Metformin and Hypoxic Stress in Colon and Lung Carcinoma Cells. Cells 2021, 10, 97. https://doi.org/10.3390/cells10010097

AMA Style

Marciano O, Mehazri L, Shpungin S, Varvak A, Zacksenhaus E, Nir U. Fer and FerT Govern Mitochondrial Susceptibility to Metformin and Hypoxic Stress in Colon and Lung Carcinoma Cells. Cells. 2021; 10(1):97. https://doi.org/10.3390/cells10010097

Chicago/Turabian Style

Marciano, Odeya, Linoy Mehazri, Sally Shpungin, Alexander Varvak, Eldad Zacksenhaus, and Uri Nir. 2021. "Fer and FerT Govern Mitochondrial Susceptibility to Metformin and Hypoxic Stress in Colon and Lung Carcinoma Cells" Cells 10, no. 1: 97. https://doi.org/10.3390/cells10010097

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