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This dissertation, Mechanistic and Functional Characterization of Bitter Melon Extract (BME) and Its Bioactive Component, MAP30, in Combating Ovarian Cancer Oncogenesis and Chemoresistance by Ming-ho, Yung, 容銘浩, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Ovarian carcinoma is one of the most leading causes of cancer death among all gynaecologic malignancies worldwide. Although there are advances in cancer treatment for the last decades, the curative rate of this disease is just modestly improved. Chemoresistance is the major obstacle in clinical management of ovarian cancer nowadays. Thus, it is an urgent need for exploring effective alternative therapeutic strategies for ovarian cancer patients with advanced or recurrent disease. Emerging evidence has suggested that targeting cancer cell metabolism is the most promising molecular therapeutic approach in combating human cancers. Recently, the application of pharmaceutical AMPK activators is a plausible approach in selectively and specifically killing cancer cells without hampering normal cells. However, these pharmaceutical AMPK activators have many side-effects. Therefore, searching for replaceable reagents from nutraceuticals is a new vista. Bitter melon and its bioactive components are proposed to be natural activator of AMPK not only to reduce triglycerides levels in hyperlipidemic diabetic or insulin-resistant rodents but also to suppress human cancer cell growth specifically without toxicity to normal cells. In this study, the anti-cancer effect and molecular mechanism of bitter melon extract (BME) and one of its bioactive components, MAP30, on ovarian cancer cells were examined. Upon treatment of BME and 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 BME or 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 BME or 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 BME and 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 BME and MAP30 functions as natural AMPK activators in suppressing cancer cells growth through activating AMPK activity and inhibiting AKT/ERK/FOXM1 signaling cascade. Importantly, this study demonstrated that BME and MAP30 induced AMPK activation through an AMP-independent manner using a pair of isogenic HEK293 cells with overexpression of either the wild-type (WT) or R531G mutant isoform of AMPK2 subunit, implying the significance that BME and MAP30 may not affect the mitochondrial respiration and thus may be more tolerated by patients when used as anti-cancer medications. Taken together, the findings in this study suggest that the non-toxic BME and 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. Thus, BME or MAP30 may be used as a supplement for synergistically enhancing the ef

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