Targeting AMPK as a valid therapeutic intervention in ovarian cancer

Abstract

Despite advances in diagnosis and treatment, the incidence of ovarian cancer is rising and the associated mortality rate has not improved significantly over the past decade. Therefore, discovery of novel targets for therapies will improve the quality of life of patients. AMP-activated protein kinase (AMPK) is an energy-sensor that maintains energy homeostasis in eukaryotic cells. Accumulating evidence has shown that AMPK activation suppresses cell proliferation in response to metabolic stress and induces apoptosis in many human cancer cells. AMPK is a heterotrimer composed of a catalytic subunit (α) and two regulatory subunits (β and γ). Our previous studies found that AMPK subunits are aberrantly expressed in ovarian cancer, and their expressions have significant correlations with ovarian cancer progression. Indeed, we have recently reported that the reduced expression of AMPK-β1 confers lower AMPK activity, which enhances the oncogenic capacity of advanced-stage ovarian cancer. Hence, we are continually studying the roles of other AMPK subunits in governing AMPK activity as well as their impact on the aggressiveness of ovarian cancer. On the other hand, emerging evidences have suggested that targeting cancer cell metabolism is a promising therapeutic approach in human cancers. Numerous studies have shown that artificially activation of AMPK by pharmaceuticals is able to block the cancer cell growth in various human cancers. Our previous studies reported that the use of pharmaceutical AMPK activators such as metformin, AICAR and A23187 could suppress cervical cancer cell growth harboring with or without LKB1, an upstream kinase of AMPK. We also proposed mechanistic evidence showing that these AMPK activators impede cervical and ovarian cancer cell growth through reducing DVL3 by AMPK/mTOR signaling, and FOXM1 through AKT/FOXO3a/FOXM1. These findings shed light on the application of AMPK activators in human cancer treatment. However, due to the undesirable outcomes along with the frequent toxic side effects of most conventional AMPK activators, further studies will investigate the potential and non-toxic natural AMPK activators as a potential supplement to improve the efficacy of patinum-based chemotherapy in ovarian cancer.