Mount Sinai Researchers Find "Removal of AKAP11 Protein by Autophagy as a key to Fuel Mitochondrial Metabolism and Tumor Cell Growth through activating protein kinase A (PKA) (Patent pending)"
Corresponding Author: Zhenyu Yue, PhD, Professor of Neurology, Aidekman Family Professorship, Director of Basic and Translational Research in Movement Disorders, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai.
Bottom Line: We uncovered a mechanism that tumor cells exploit selective autophagy for metabolic reprogramming that benefits tumor cell growth and offers resistance to glucose deprivation. Our study suggests that AKAP220-mediated autophagy as a novel therapeutic target for specific cancer treatment.
Results: Autophagy is a lysosome degradation pathway that is cytoprotective through recycling of intracellular cargoes and supplying the breakdown products. We now show a novel mechanism that autophagy selectively degrades PKA inhibitory subunit RIa, which is mediated through AKAP11 receptor in response to energy crisis. The AKAP11-mediated degradation of RIa and cAMP/PKA activation result in heightened mitochondrial metabolism in response to glucose starvation and subsequent protection of cell survival. Importantly, we show that suppression of AKAP11 levels in tumor cells prevents the degradation of RIa and blocks PKA activation, therefore causing inhibition of tumor cell growth.
Why the Research Is Interesting: Our study shows a new concept of autophagy-mediated cell protection and tumor growth by disinhibiting protein kinase A (PKA), a master regulator of cell metabolism, and promoting mitochondria metabolic rewiring. Multiple lines of evidence demonstrate activation of PKA in tumors and activation of PKA drives tumorigenesis. Our studies reveal a novel therapeutic target in the treatment of certain cancers by blocking autophagy-mediated PKA activation.
Study Conclusions: Our study uncovers a cytoprotection mechanism whereby autophagy controls cell metabolism beyond production of digested nutrient for cell replenishment and survival. We identify a critical role of autophagy in boosting the activity of cAMP/PKA, a master regulator of cell metabolism, to maintain cell survival during energy crisis. We show that autophagy selectively degrades PKA inhibitory subunit RIα, which is mediated through AKAP11 receptor. The AKAP11 - mediated cAMP/PKA activation result in heightened mitochondrial metabolism in response to glucose starvation and subsequent protection of cell survival. We also show that suppression of AKAP11 levels in tumor cells prevents the degradation of RIα and consequently blocks PKA activation, therefore causing inhibition of tumor cell growth. We conclude that tumor cells exploit selective autophagy that degrades AKAP11 and activates PKA for their growth and resistance to glucose deprivation.
Paper Title: Selective Autophagy of AKAP11 Activates cAMP/PKA to Fuel Mitochondrial Metabolism and Tumor Cell Growth
Said Mount Sinai's Dr. Zhenyu Yue of the research:
"Our results thed a light on autophagy protection mechanism by demonstrating a critical function of autophagy in fueling the mitochondrial metabolism and conferring cell resistance to glucose deprivation in growth. Our studies thus reveal a novel therapeutic target of AKAP11 selective autophagy in the treatment of certain cancers."
Deng, Z., et al. (2021) Selective autophagy of AKAP11 activates cAMP/PKA to fuel mitochondrial metabolism and tumor cell growth. PNAS. doi.org/10.1073/pnas.2020215118.