GABARAPL2 and Alix mediate reciprocal regulation of autophagy and exosome pathways to facilitate cellular homeostasis.

backgroundThe continuous reliance of cancer cells on acquiring energy and communicating their nutrient needs makes them both resilient and vulnerable. It provides an opportunity to stifle cancer cells by restricting their energy generation and communication ability. Autophagy and exosome biogenesis pathways are essential in maintaining the robust growth and survival of cancer cells. METHOD &

resultsIn this study, we observed that inhibiting one pathway altered gene expression in the other pathway. Exosome biogenesis, when blocked, led to an increase in breast cancer cell proliferation, while inhibition of autophagy did not significantly affect cancer cell proliferation. The two pathways, when inhibited independently, did not have a significant effect on restricting cancer cell growth. However, a combined inhibition of both pathways led to a substantial reduction in cancer cell proliferation. To evaluate the reciprocal regulation of two pathways, we blocked the autophagy pathway and observed increased exosome release from MDA-MB-231 cells, accompanied by decreased expression of Alix and CD63. In contrast, inhibition of exosome biogenesis led to increased expression of ATG5 and ATG16L1 and a significant decrease in GABARAPL2 expression. Interestingly, the knockdown of GABARAPL2 abrogated the decrease in Alix expression upon autophagy inhibition, highlighting the essential role of GABARAPL2 in Alix secretion.

conclusionThus, our study highlights, for the first time, the synergistic effects of autophagy and exosome pathway inhibition in restricting cancer cell growth, as well as the involvement of GABARAPL2 in regulating exosome secretion by modulating Alix expression.