Suppression of mitochondrial respiration with auraptene inhibits the progression of renal cell carcinoma: involvement of HIF-1α degradation

// Yunseon Jang 1 , Jeongsu Han 1 , Soo Jeong Kim 1 , Jungim Kim 1 , Min Joung Lee 1 , Soyeon Jeong 1 , Min Jeong Ryu 1, 2 , Kang-Sik Seo 3 , Song-Yi Choi 4 , Minho Shong 5 , Kyu Lim 1, 2 , Jun Young Heo 1, 6 , Gi Ryang Kweon 1, 2 1 Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747 2 Research Institute for Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747 3 R&D center, KT&G Life Sciences 4 Department of Pathology, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747 5 Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747 6 Brain research institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747 Correspondence to: Gi Ryang Kweon, e-mail: mitochondria@cnu.ac.kr Jun Young Heo, e-mail: junyoung3@gmail.com Keywords: auraptene, renal cell carcinoma, HIF-1α, mitochondrial respiration, eIF2α Received: April 03, 2015      Accepted: September 29, 2015      Published: October 12, 2015 ABSTRACT 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.