Abstract 4455: Metabolic stress induces a double positive feedback loop between AMPK and p62 conferring dual activation of AMPK and NRF2 to synergize antioxidant defense

Abstract Co-occurring mutations in KEAP1 in LKB1-mutant NSCLC activate NRF2 to compensate losing LKB1-AMPK activity during metabolic adaptation and survival. Here, we investigated the regulatory crosstalk between LKB1-AMPK and KEAP1-NRF2 pathways during metabolic stress. We found that metabolic stress activates NRF2 through the expression and phosphorylation of p62, causing the autophagic degradation of KEAP1. Intriguingly, the induction of p62 during metabolic stress is also required to activate AMPK by promoting AXIN-LKB1-AMPK complex formation and recruiting it to the lysosomal membrane. Importantly, the p62-driven dual-activation of AMPK and NRF2 was critical for tumour growth by synergizing antioxidant defences. In turn, the induction of p62 also required LKB1-AMPK activity, suggesting a double positive feedback loop between AMPK and p62. Mechanistically, the increase in lysosomal pH caused by low glucose metabolism and AMPK-dependent reduction of proton generation induced PP2A-dependent dephosphorylation of TFEB/TFE3 which increased the expression of p62. The increase of ROS caused by metabolic stress induced lysosomal MCOLN1-Ca2+ dependent activation of TAK1 which increased p62 phosphorylation. Protons provided by lactic acid abrogated all the effects caused by metabolic stress. This positive feedback loop between AMPK and p62 that activates AMPK and NRF2 can potentially explain why co-occurring mutations in LKB1 and KEAP1 occur and further provide promising therapeutic strategies for lung cancer. Citation Format: Eun-Ji Choi, Hyun-Taek Oh, Seon-Hyeong Lee, Chen-Song Zhang, Mengqi Li, Soo-Youl Kim, Sunghyouk Park, Tong-Shin Chang, Byung-Hoon Lee, Sheng-Cai Lin, Sang-Min Jeon. Metabolic stress induces a double positive feedback loop between AMPK and p62 conferring dual activation of AMPK and NRF2 to synergize antioxidant defense abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4455.