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Abstract
GABARAPL1/GEC1 is an early estrogen-induced gene which encodes a protein highly conserved from C. elegans to humans. Overexpressed GABARAPL1 interacts with GABAA or kappa opioid receptors, associates with autophagic vesicles, and inhibits breast cancer cell proliferation. However, the function of endogenous GABARAPL1 has not been extensively studied. We hypothesized that GABARAPL1 is required for maintaining normal autophagic flux, and plays an important role in regulating cellular bioenergetics and metabolism. To test this hypothesis, we knocked down GABARAPL1 expression in the breast cancer MDA-MB-436 cell line by shRNA. Decreased expression of GABARAPL1 activated procancer responses of the MDA-MB-436 cells including increased proliferation, colony formation, and invasion. In addition, cells with decreased expression of GABARAPL1 exhibited attenuated autophagic flux and a decreased number of lysosomes. Moreover, decreased GABARAPL1 expression led to cellular bioenergetic changes including increased basal oxygen consumption rate, increased intracellular ATP, increased total glutathione, and an accumulation of damaged mitochondria. Taken together, our results demonstrate that GABARAPL1 plays an important role in cell proliferation, invasion, and autophagic flux, as well as in mitochondrial homeostasis and cellular metabolic programs.
Disclosure of Potential Conflicts of Interest
VDU is a member of the Seahorse Biosciences Scientific Advisory Board.
Acknowledgment
Michaël Boyer-Guittaut would like to thank his colleagues from the EA3922 team, Jacques Bahi, president of the Université of Franche-Comté, Abderrazzak Kadmiri, director of UFR-ST of the Université of Franche-Comté and the Université of Franche-Comté for their support during this research project performed at the University of Alabama in Birmingham, AL, USA. Laura Poillet is supported by a fellowship of the Région de Franche-Comté. The authors acknowledge funding from the following sources: Dr Jianhua Zhang was supported by NIHR01-NS064090 and a VA merit award. Flow cytometry was supported by RDCC-APCC core (NIH P30 grant #P30 AR48311). The authors would like to thank Enid F Keyser (UAB Flow cytometry core, Birmingham, AL) for her technical help using the LSR-II Becton Dickinson flow cytometer. Authors are grateful to Jianhua Zhang’s and Victor M Darley-Usmar’s laboratory members for their technical help, advice, and critical reviewing of this manuscript.