Phosphorylation of PDHA by AMPK Drives TCA Cycle to Promote Cancer Metastasis

Abstract

Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.

Control of topoisomerase II activity and chemotherapeutic inhibition by TCA cycle metabolites

“…TCA cycle metabolites are key anabolic precursors and citrate, in particular, is critical to support elevated levels of lipid biosynthesis in cancer cells (Li and Cheng, 2014; Menendez and Lupu, 2007). Recent studies have also found that the impairment of TCA cycle metabolism and OXPHOS can decrease tumorigenic and metastatic potential (Cai et al, 2020; Cavalli et al, 1997; Lebleu et al, 2014; Morais et al, 1994; Tan et al, 2015). These findings demonstrate that cancer cells not only maintain active TCA cycle metabolism but are dependent on it.…”

A redox-dependent mechanism for AMPK dysregulation interrupts metabolic adaptation of cancer under glucose deprivation

“…This process activates mitochondrial OXPHOS, providing an alternative source of ATP and NADPH 4, 53 . Also, AMPK facilitates the TCA cycle by direct phosphorylation of pyruvate dehydrogenase, which improves cancer cells’ adaptation to the metastatic environment for breast cancers 19 . AMPK regulates T cell metabolic adaptation by glutamine-dependent mitochondrial metabolism in a glucose-limited environment 54 .…”

“…Therefore, proper AMPK activation is required for overcoming metabolic stress. For instance, AMPK protects leukemia-initiating cells from metabolic stress 18 , promotes cancer metastasis 19 and mediates anoikis resistance 20 , whereas LKB1-null cancers are highly vulnerable to energetic stress due to failure of metabolic adaptation 4, 21 . Thus, understanding different AMPK regulation of glucose addicted versus resistant cancer cells under metabolic stress would be necessary for gaining insight for glucose metabolism targeting therapeutic intervention.…”

Early Heat Exposure Effects on Proteomic Changes of the Broiler Liver under Acute Heat Stress

“…In our study, HS altered six proteins (CAT1, DLD, LDHB, ME1, PCK1, and PDHA1) compared with the control, and early heat exposure ameliorated all six proteins. Among the six proteins, HS resulted in decreased PDHA1 (PDH complex) expression in pyruvate metabolism, likely leading to reduced oxidative phosphorylation of pyruvate, and pyruvate that does not enter the oxidative phosphorylation process is synthesized into l-lactate due to the increased LDHB (L-Lactate dehydrogenase B) by HS [ 21 ]. However, the expression levels of these proteins were ameliorated to a level similar to that of the control in the early heat exposure group.…”