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

Simple Summary TRAF6-BECN1 signaling axis in TLR4 signal plays an essential role for the autophagy induction, thereby it regulates cancer migration and invasion. Here we show that AMPK alpha 1, one of the isoforms of AMPK, is functionally involved in autophagy induction by regulating the TRAF6-BECN1 signaling axis. In this context, AMPK alpha 1-knockout lung or breast cancer cells exhibited the attenuation of cancer cell migration and invasion induced by TLR4 simulation. Additionally, we could find that the expression of AMPK alpha 1 is positively associated with gene expressions related to autophagy, migration, and metastasis of cancer cells in primary non-small cell lung cancers (NSCLCs). These findings demonstrate that AMPK alpha 1 plays a pivotal role in cancer progression by regulating the TRAF6-BECN1 signaling axis for autophagy induction. 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.