Functional characterization of MAP30 protein from bitter melon (Momordica charantia) in combating ovarian cancer oncogenesis and chemoresistance

Abstract

Ovarian cancer is one of the most lethal gynaecological malignancies. Most ovarian cancer cases carry a poor prognosis and many patients succumb to late-stage disease. Platinum-based drugs such as cisplatin are the most potent anti-tumor agents commonly used to treat advanced ovarian cancers. However, the major limitations of these drugs include the acquisition of resistance in initially responsive tumors and serious side effects with high doses. Thus, the exploration of alternative anti-cancer approaches, such as the use of foods and herbal supplements in combination with current chemotherapy, is urgently needed to improve the treatment efficacy of available drugs. AMPK is a metabolic energy sensor that governs energy homeostasis in cells. Recently, we and others found that low AMPK activity favours cancer cell growth, while treatment with AMPK activators such as AICAR or metformin were found to remarkably inhibit cell growth. Increasing evidence has shown that Traditional Chinese Medicine (TCM) has a noticeable choice for cancer treatment, while there is still lack of scientific investigation of its underlying molecular mechanisms. Bitter melon (Momordica charantia) is a traditional dietary fruit, but its extract also shows potential medicinal uses in human diabetes and cancers. Recently, emerging evidence has suggested that bitter melon extract (BME) could function similarly to natural AMPK with regard to human cancer cell growth suppression and apoptosis induction, without toxic effects against normal cells. In particular, Momordica anti-HIV protein (MAP30), one of the most bioactive components in BME, while its effect on anti-tumorigenesis and anti-chemoresistance remains unclear. In this study, we found that MAP30 could inhibit ovarian cancer cell proliferation and increase cell apoptosis in a dose dependent manner. Additionally, it is known that tumor microenvironement is 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.