Abstract 786: Metastasis is driven by mitochondrial protein A via mitochondrial reprogramming in colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) is the third most common cancer worldwide, and CRC metastasis is the main cause of cancer-associated mortality. The hypoxia signaling pathway controls mediators to facilitate cancer progression and metastasis. Recently, mitochondrial reprogramming has emerged as a one of the mechanisms of hypoxia-induced metastasis; however, the link between hypoxia-induced metastasis and mitochondrial reprogramming remains to be elucidated. Here, we have focused on the novel mitochondrial protein A, to determine its role in the molecular mechanism of hypoxia-induced metastasis. Our results indicate that mitochondrial protein A is a downstream target of hypoxia-inducible factor 1 (HIF-1α) and plays an essential role in HIF-1-induced migration and invasion. In addition, we found a clinical correlation between hypoxia and mitochondrial protein A. To identify the role of mitochondrial protein A, we generated mitochondrial protein A deficient or silenced cells, which showed impaired migration, invasion, and colony-forming ability even under hypoxic condition. In contrast, ectopic expression of mitochondrial protein A elevated metastatic potential, both in vitro and in vivo. Mechanistically, mitochondrial protein A directly interacted with dynamin-related protein (DRP1) to retain it in mitochondria, thereby promoting mitochondrial fission. To confirm the effect of mitochondrial fission on mitochondrial protein A-induced metastasis, we blocked DRP1 in mitochondrial protein A overexpressing cells by pharmacological inhibition, which led to impairment of mitochondrial protein A-induced metastatic potential. Furthermore, mitochondrial protein A-silenced cells showed decreased metabolism and lactate production, suggesting that mitochondrial protein A regulates the mitochondrial reprogramming. In summary, we demonstrate that mitochondrial protein A is a novel DRP1 adaptor protein, facilitating mitochondrial fission and mitochondrial reprogramming, and plays a critical role in hypoxia-induced metastasis. We suggest that targeting of mitochondrial protein A maybe a strategy for cancer therapy. Citation Format: Dayeon Kim, Sang-Mo Kwon. Metastasis is driven by mitochondrial protein A via mitochondrial reprogramming in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 786.