AMPKα1 Regulates Lung and Breast Cancer Progression by Regulating TLR4-Mediated TRAF6-BECN1 Signaling Axis

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 (AMPK&alpha
1, PRKAA1) is positively involved in autophagy induction and cancer progression by regulating TRAF6-BECN1 signaling axis. Mechanistically, AMPK&alpha
1 interacted with TRAF6 and BECN1. It also enhanced ubiquitination of BECN1 and autophagy induction. AMPK&alpha
1-knockout (AMPK&alpha
1KO) HEK293T or AMPK&alpha
1-knockdown (AMPK&alpha
1KD) THP-1 cells showed impaired autophagy induced by serum starvation or TLR4 (Toll-like receptor 4) stimulation. Additionally, AMPK&alpha
1KD THP-1 cells showed decreases of autophagy-related and autophagosome-related genes induced by TLR4. AMPK&alpha
1KO A549 cells exhibited attenuation of cancer migration and invasion induced by TLR4. Moreover, primary non-small cell lung cancers (NSCLCs, n = 6) with low AMPK&alpha
l 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 (n = 5) with high AMPK&alpha
l levels. Consistently, attenuation of cancer migration and invasion could be observed in AMPK&alpha
1KO MDA-MB-231 and AMPK&alpha
1KO MCF-7 human breast cancer cells. These results suggest that AMPK&alpha
1 plays a pivotal role in cancer progression by regulating the TRAF6-BECN1 signaling axis for autophagy induction.