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.
Highlights
Metastasis is the main cause of death among cancer patients, and targeting the metastatic process is one of the major challenges in current cancer therapy.Increasing evidence suggests that migrating cancer cells and primary tumor cells utilize distinct metabolic pathways [1,2,3,4]
To decipher the roles of Fer and FerT in modulating mitochondria susceptibility to stress cues in cancer cells, we initially focused on metastatic SW620 colon cancer (CC)
To test the impact of Fer and FerT absence on the sensitivity of SW620 cells to the mitochondrial targeting effect of metformin, SW∆Fer/FerT cells were cultured in a medium devoid of glucose and supplemented with glutamine
Summary
Metastasis is the main cause of death among cancer patients, and targeting the metastatic process is one of the major challenges in current cancer therapy. Increasing evidence suggests that migrating cancer cells and primary tumor cells utilize distinct metabolic pathways [1,2,3,4]. Analysis of gene expression signatures in an orthotopic breast cancer model indicated that circulating tumor cells are enriched in factors that regulate mitochondrial respiration and biogenesis compared with primary and metastatic lesions [2]. The mitochondria of cancer cells are reprogrammed and modified compared to normal cells. The mitochondrial glutamine uptake machinery which propels the tricarboxylic acid (TCA) cycle is upregulated in cancer cells [5,6]. Other functional pathways including the electron transport chain (ETC)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
