AMP-activated protein kinase gamma-2 (AMPK-g2) subunit modulates AMPK activities to ensure ovarian cancer progression

Abstract

Targeting cancer cell metabolism with chemotherapeutics is a new promising strategy to improve cancer treatment. AMP-activated protein kinase (AMPK) is a heterotrimeric Ser/Thr kinase complex that consists of a catalytic α subunit and two regulatory subunits (β, γ), and acts as an energy-sensor to govern cancer cell metabolism. How of their expressions codifying of AMPK activity and cancer cell metabolism in tumor progression remain unclear. Our previous study reported that AMPK subunits are diversely expressed during ovarian cancer progression while their impact on ovarian cancer oncogenesis during tumor progression is obscure. Here, we show that the AMPK-γ2 subunit (γ2) is frequently upregulated and is inversely correlated with AMPK activity in advanced ovarian cancer. Overexpression of γ2 enables to suppress AMPK/mTOR signaling, promotes oncogenic capacities in ovarian cancer cells, and attenuates AICAR-induced cell growth retardation (AICAR is the common pharmacologic AMPK activator). Mechanistic studies revealed that AMPK-α1/2, -β1 and -γ1 subunits are predominantly forming AMPK trimeric complexes, while a substantial proportion of γ2 acts as a free form and enables to compete with the AMPK complex for AMP/ZMP binding that in turns, suppresses AMPK activation. Clinico-pathological analysis demonstrated that the overexpressed AMPK-γ2 was inversely correlated with lower AMPK activity in advanced and high-graded ovarian cancers, suggesting the expression status of AMPK-γ2 is clinically relevance. Taken together, these findings suggest γ2 prefers to exist as a fine turner to modulate AMPK activities favoring oncogenic properties of ovarian cancers during tumor progression.