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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Human mitochondrial NAD(P)(+)-dependent malic enzyme participates in cutaneous melanoma progression and invasion
Yung-Lung Chang1, Hong-Wei Gao2, Chien-Ping Chiang3
1Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan; Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan.
Abstract:
Cutaneous melanoma is the most life-threatening neoplasm of the skin, accounting for most of the skin cancer deaths. Accumulating evidence suggests that targeting metabolism is an appealing strategy for melanoma therapy. Mitochondrial NAD(P)(+)-dependent malic enzyme (ME2), an oxidative decarboxylase, was evaluated for its biological significance in cutaneous melanoma progression. ME2 mRNA and protein expression significantly increased during melanoma progression, as evidenced by Gene Expression Omnibus analysis and immunohistochemistry on clinically annotated tissue microarrays, respectively. In addition, ME2 knockdown attenuated melanoma cell proliferation in vitro. ME2 ablation resulted in reduced cellular ATP levels and elevated cellular reactive oxygen species production, which activated the AMP-activated protein kinase pathway and inhibited acetyl-CoA carboxylase. Furthermore, ME2 expression was associated with cell migration and invasion. ME2 knockdown decreased anchorage-independent growth in vitro and tumor cell growth in vivo. These results suggested that ME2 might be an important factor in melanoma progression and a novel biomarker of invasion.
Insights
Mitochondrial malic enzyme 2 (ME2) is upregulated in melanoma, driving cancer progression and invasion. Inhibiting ME2 reduces melanoma cell growth and metastasis, suggesting ME2 as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cutaneous melanoma is a deadly skin cancer.
- Targeting cancer metabolism is a promising therapeutic strategy.
- The role of mitochondrial NAD(P)(+)-dependent malic enzyme 2 (ME2) in melanoma is unclear.
Purpose of the Study:
- To investigate the biological significance of ME2 in cutaneous melanoma progression.
- To determine if ME2 is a potential therapeutic target or biomarker for melanoma.
Main Methods:
- Analysis of ME2 mRNA and protein expression in melanoma tissues using Gene Expression Omnibus and immunohistochemistry.
- In vitro studies involving ME2 knockdown in melanoma cells to assess proliferation, ATP levels, reactive oxygen species (ROS) production, and migration.
- In vivo studies to evaluate the effect of ME2 knockdown on tumor growth.
Main Results:
- ME2 expression significantly increases with melanoma progression.
- ME2 knockdown reduces melanoma cell proliferation, ATP levels, and increases ROS production.
- ME2 inhibition activates the AMP-activated protein kinase (AMPK) pathway.
- ME2 expression correlates with increased cell migration, invasion, anchorage-independent growth, and tumor growth in vivo.
Conclusions:
- ME2 plays a critical role in melanoma progression and invasion.
- ME2 is a potential therapeutic target for melanoma.
- ME2 may serve as a novel biomarker for melanoma invasion.
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