Suppression of mitochondrial respiration with auraptene inhibits the progression of renal cell carcinoma: involvement of HIF-1α degradation
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Yunseon Jang1, Jeongsu Han1, Soo Jeong Kim1, Jungim Kim1, Min Joung Lee1, Soyeon Jeong1, Min Jeong Ryu1,2, Kang-Sik Seo3, Song-Yi Choi4, Minho Shong5, Kyu Lim1,2, Jun Young Heo1,6, Gi Ryang Kweon1,2
1Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747
2Research Institute for Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747
3R&D center, KT&G Life Sciences
4Department of Pathology, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747
5Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747
6Brain research institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747
Gi Ryang Kweon, e-mail: firstname.lastname@example.org
Jun Young Heo, e-mail: email@example.com
Keywords: auraptene, renal cell carcinoma, HIF-1α, mitochondrial respiration, eIF2α
Received: April 03, 2015 Accepted: September 29, 2015 Published: October 12, 2015
Renal cell carcinoma (RCC) progression resulting from the uncontrolled migration and enhanced angiogenesis is an obstacle to effective therapeutic intervention. Tumor metabolism has distinctive feature called Warburg effect, which enhances the aerobic glycolysis rapidly supplying the energy for migration of tumor. To manipulate this metabolic change characteristic of aggressive tumors, we utilized the citrus extract, auraptene, known as a mitochondrial inhibitor, testing its anticancer effects against the RCC4 cell line. We found that auraptene impaired RCC4 cell motility through reduction of mitochondrial respiration and glycolytic pathway-related genes. It also strongly disrupted VEGF-induced angiogenesis in vitro and in vivo. Hypoxia-inducible factor 1a (HIF-1a), a key regulator of cancer metabolism, migration and angiogenesis that is stably expressed in RCCs by virtue of a genetic mutation in the von Hippel–Lindau (VHL) tumor-suppressor protein, was impeded by auraptene, which blocked HIF-1a translation initiation without causing cytotoxicity. We suggest that blockade HIF-1a and reforming energy metabolism with auraptene is an effective approach for suspension RCC progression.
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