The Functional Role of Human Malic Enzymes in Melanoma Tumorigenesis

• Main Authors: Yung-Lung Chang, 張永龍
• Other Authors: 洪慧芝
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/72188339467895884281

博士 === 國立中興大學 === 生命科學系所 === 103 === Cutaneous melanoma is the most life-threatening neoplasm of the skin, accounting for most skin cancer deaths. Accumulating evidence suggests that targeting metabolism is an appealing strategy for melanoma therapy. Malic enzyme is a metabolic enzyme that catalyzes the decarboxylation reaction to generate pyruvate from malate. Malic enzyme consists of three isoforms, ME1, ME2 and ME3, which differ in their cofactor preference and subcellular localization. Among these isoforms, ME2 has been implicated to be associated with tumor metabolism for decades, but few studies dedicated to its functional role in cancer biology. Herein, we investigated the expression of three malic enzyme isoforms in melanoma. In two previously reported datasets from Gene Expression Omnibus (GEO), ME2 mRNA expression was upregulated in malignant melanoma compared to normal/benign specimens, whereas ME1 and ME3 mRNA levels in melanoma were lower than that in normal/benign tissues. Furthermore, ME2 protein levels increased with melanoma tumor progression by immunehistochemistry on clinically annotated tissue microarrays. Depletion of endogenous ME2 by shRNAs significantly impaired melanoma cell proliferation in vitro. ME2 ablation decreased cellular ATP levels and increased Reactive Oxygen Species (ROS) production, which activated the AMP-activated protein kinase (AMPK) pathway. Moreover, ME2 expression was correlated with cell migration and invasion. ME2 knockdown reduced anchorage-independent growth in vitro and tumor cell growth in vivo. These results revealed that ME2 play an important role in melanoma metabolic profiling and tumor progression.