Rethinking AMPK: A Reversible Switch Fortifying Cancer Cell Stress-Resilience.

Stress adaptation is an evolutionarily conserved mechanism that promotes survival in the face of adverse conditions. AMP-activated protein kinase (AMPK) is a highly conserved energy-sensing kinase found in nearly all eukaryotic cells. It maintains energy homeostasis by promoting catabolism and inhibiting anabolism. In the context of cancer, the role of AMPK is controversial. It was initially touted as a tumor suppressor due to its association with Liver Kinase B1 (LKB1) (an upstream regulator and a known tumor suppressor) and ensuing growth-suppressive actions. However, emerging studies across a variety of cancer types unambiguously reveal AMPK's pro-survival and, thus, tumor-promoting activity, especially under cancer-associated stresses such as hypoxia, nutrient deprivation, oxidative stress, matrix detachment, and chemotherapy. In cancer cells, AMPK is activated in response to stress-induced increases in the levels of adenosine monophosphate (AMP), Ca²⁺, or reactive oxygen species (ROS). Upon activation, AMPK engages in metabolic rewiring and crosstalk with signaling molecules to mobilize resources toward survival while compromising proliferation. Here, we posit that AMPK is a non-genetic "reversible switch," allowing cancer cells' phenotype to switch to dormant, stem-like, and drug-resistant states, thereby enabling tumor cell survival, pathological progression, and therapy resistance. This review underscores the critical role of AMPK in driving cancer cell stress resilience and survival, advocating for the strategic use of AMPK inhibitors to improve cancer treatment outcomes.