Abstract 878: Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation
Authors: Boyle Kathleen A. , VanWickle Jonathan , Zielonka Jacek , Cheng Gang , Kalyanaraman Balaraman , Dwinell Michael B. 
Published: August 2018

In the US, colorectal cancer is predicted to afflict 1 out of every 20 people and is the third major cause of cancer. The first line of treatment for localized colorectal tumors is surgical resection, while perioperative chemo- and/or radiation-therapy is administered upon disease metastasis. These cytotoxic treatments may have pronounced side-effects and off-target consequences. A major caveat to these treatment regimens is that their efficacy is restricted to tumors that express wild-type KRAS protein. KRAS is a common genetic mutation, accounting for ~50 % of colorectal cancer oncogenic mutations. Thus, there remains a significant need for therapies with increased efficacy, reduced toxicity and directed tumor specificity, particularly in the context of KRAS oncogene expression. With the continuing demonstration that mitochondrial metabolism is a key player in cancer development, progression and metastasis, it is rational to exploit this observation and explore mitochondrial targeted compounds as novel, untapped therapeutics. Indeed, several reports have shown that compounds targeted to the mitochondria induce anti-proliferative and cytotoxic effects in tumor cells without a significant impact on normal cells. We sought to exploit mitochondria-targeted cationic drugs that selectively inhibit energy metabolism in cancer cells as treatment of KRAS mutant colorectal cancer. The anti-cancer mechanisms of Mito-CP and Mito-Met, two mitochondria-targeted drugs we have shown to block bioenergetic metabolism, were examined in wild-type and oncogenic KRAS-expressing colon cancer cells. Mitochondrial function, intracellular ATP levels, cellular uptake, energy sensor signaling and functional effects on cancer cell growth were assayed. Both Mito-CP and Mito-Met depleted intracellular ATP and caused prolonged inhibition of ATP-linked oxygen consumption in colon cancer cells. The anti-proliferative effects reflected the activation of AMPK and the phosphorylation-mediated inhibition of the mTORC1-target p70S6K. Moreover, Mito-CP and Mito-Met released the autophagy regulator ULK1 from mTORC1-mediated inhibition, leading to mitophagy. Inhibition of AMPK and mTORC1 signaling mitigated the anti-proliferative effects of these mitochondria-targeted compounds. These data are the first demonstration that drugs selectively targeting the cancer cell mitochondria induce mitophagy. Given the resistance of KRAS colon cancer tumors to immunotherapeutic agents, targeting bioenergetic metabolism using mitochondria-targeted agents to stimulate mitophagy provides an attractive novel approach for therapeutic intervention.

Citation Format: Kathleen A. Boyle, Jonathan VanWickle, Jacek Zielonka, Gang Cheng, Balaraman Kalyanaraman, Michael B. Dwinell. Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 878.