| Summary: | TRAF6-BECN1 signaling axis is critical for autophagy induction and functionally implicated in cancer progression. Here, we report that AMP-activated protein kinase alpha 1 (<i>AMPKα1</i>, <i>PRKAA1</i>) is positively involved in autophagy induction and cancer progression by regulating TRAF6-BECN1 signaling axis. Mechanistically, AMPKα1 interacted with TRAF6 and BECN1. It also enhanced ubiquitination of BECN1 and autophagy induction. <i>AMPKα1</i>-knockout (<i>AMPKα1</i>KO) HEK293T or <i>AMPKα1</i>-knockdown (<i>AMPKα1</i>KD) THP-1 cells showed impaired autophagy induced by serum starvation or TLR4 (Toll-like receptor 4) stimulation. Additionally, <i>AMPKα1</i>KD THP-1 cells showed decreases of autophagy-related and autophagosome-related genes induced by TLR4. <i>AMPKα1</i>KO A549 cells exhibited attenuation of cancer migration and invasion induced by TLR4. Moreover, primary non-small cell lung cancers (NSCLCs, <i>n</i> = 6) with low AMPKαl levels showed markedly decreased expression of genes related to autophagy, cell migration and adhesion/metastasis, inflammation, and TLRs whereas these genes were significantly upregulated in NSCLCs (<i>n</i> = 5) with high AMPKαl levels. Consistently, attenuation of cancer migration and invasion could be observed in <i>AMPKα1</i>KO MDA-MB-231 and <i>AMPKα1</i>KO MCF-7 human breast cancer cells. These results suggest that AMPKα1 plays a pivotal role in cancer progression by regulating the TRAF6-BECN1 signaling axis for autophagy induction.
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