Identification of MAP30 as a natural AMPK activator in targeting the tumorigenicity and chemoresistance of ovarian cancer cells

Abstract

Ovarian carcinoma is one of the most leading causes of cancer death among all gynaecologic malignancies worldwide. Emerging evidence has suggested that targeting cancer cell metabolism is a promising molecular therapeutic approach in combating human cancers. Recently, the application of pharmaceutical AMPK activators as potential curative regimes has attracted many attentions, while the efficacies of these activators and side effects are varied. In this study, the anti-cancer effect and molecular mechanism of MAP30, a bioactive component of bitter melon, on ovarian cancer cells were examined. Upon treatment of MAP30, ovarian cancer cells showed a drastic reduction in cell proliferation and an increase of cell apoptosis in a dose dependent manner. Intriguingly, co-treatment of MAP30 could enhance cisplatin-induced cell cytotoxicity in ovarian cancer cells. On the other hand, tumor microenvironement has been known as a key factor promoting cancer progression and chemoresistance. Results herein showed that MAP30 could inhibit cell growth, cell migration and invasion of ovarian cancer cells mediated by omentum conditioned medium (OCM), as well as enhanced cisplatin-mediated cell cytotoxicity in a xenograft mouse tumour model. Mechanistic studies revealed that the inhibitory effect of MAP30 was concomitantly associated with up-regulated AMPK activity but reduced expression of phospho-AKT, phospho-ERK and FOXM1. Such effects were similar to the functions of common AMPK activators e.g. AICAR, A23187, metformin or hypoxic stress, indicating that MAP30 functions as natural AMPK activator in suppressing cancer cells growth via activating AMPK activity and inhibiting AKT/ERK/FOXM1 signaling. Importantly, this study demonstrated that MAP30 induced AMPK activation through an AMP-independent manner, implying the significance that MAP30 may not affect the mitochondrial respiration and thus may be more tolerated by patients when used as anti-cancer medications. Taken together, findings here suggest that the MAP30 function as natural AMPK activator in impairing ovarian cancer cell growth and enforcing cisplatin-mediated cell cytotoxicity in ovarian cancer cells through targeting cancer cell metabolism.