Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44. Issue 2 (14th November 2016)

• Record Type: Journal Article
• Authors: Huang, Yinghui; Zhou, Jie; Luo, Shenglin; Wang, Yang; He, Jintao; Luo, Peng; Chen, Zelin; Liu, Tao; Tan, Xu; Ou, Juanjuan; Miao, Hongming; Liang, Houjie; Shi, Chunmeng
• Is Part Of: Gut. Volume 67:Issue 2(2018)
• Page Start: 307
• Page End: 319
• Publication Date: 2016-11-14
• Subjects: COLORECTAL CANCER -- MOLECULAR MECHANISMS -- PHARMACOTHERAPY; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2016-311909
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: As the modulation of autophagic processes can be therapeutically beneficial to cancer treatment, the identification of novel autophagic enhancers is highly anticipated. However, current autophagy-inducing anticancer agents exert undesired side effects owing to their non-specific biodistribution in off-target tissues. This study aims to develop a multifunctional agent to integrate cancer targeting, imaging and therapy and to investigate its mechanism. Design: A series of mitochondria-targeting near-infrared (NIR) fluorophores were synthesised, screened and identified for their autophagy-enhancing activity. The optical properties and biological effects were tested both in vitro and in vivo. The underlying mechanism was investigated using inhibitors, small interfering RNA (siRNA), RNA sequencing, mass spectrometry and human samples. Results: We have screened and identified a new NIR autophagy-enhancer, IR-58, which exhibits significant tumour-selective killing effects. IR-58 preferentially accumulates in the mitochondria of colorectal cancer (CRC) cells and xenografts, a process that is glycolysis-dependent and organic anion transporter polypeptide-dependent. IR-58 kills tumour cells and induces apoptosis via inducing excessive autophagy, which is mediated through the reactive oxygen species (ROS)-Akt-mammalian target of rapamycin (mTOR) pathway. RNA sequencing, mass spectrometry and siRNA interference studies demonstrate that translocase of inner mitochondrial membrane 44 (TIM44)-superoxide dismutase 2 (SOD2) pathway inhibition is responsible for the excessive ROS, autophagy and apoptosis induced by IR-58. TIM44 expression correlates positively with CRC development and poor prognosis in patients. Conclusions: A novel NIR small-molecule autophagy-enhancer, IR-58, with mitochondria-targeted imaging and therapy capabilities was developed for CRC treatment. Additionally, TIM44 was identified for the first time as a potential oncogene, which plays an important role in autophagy through the TIM44-SOD2-ROS-mTOR pathway.