Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44

Huang, Yinghui; Zhou, Jie; Luo, Shenglin; Wang, Yang; He, Jintao; Luo, Peng; Chen, Zelin; Liu, Tao; Tan, Xu; Ou, Juanjuan; Miao, Hongming; Liang, Houjie; Chen, Shi

doi:10.1136/gutjnl-2016-311909

Cited by 52 publications

(34 citation statements)

References 41 publications

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“…Yuan et al reported that a strong IR‐783 signal was detected in prostate cancer tissues but not in normal tissues, and their research showed that IR‐783 staining was almost completely colocalized with MitoTracker (a mitochondrial‐selective probe) in cancer cells. Moreover, they also identified that the organic anion transporter polypeptide (OATP), which is highly expressed in cancer cells, mediates the uptake of heptamethine cyanine dyes such as IR‐780, MHI‐148 and IR58 into the mitochondria of tumour cells. These results all suggest that the anticancer property of IR‐783 is related to mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Tang

Liu

Zhang

et al. 2018

J Cellular Molecular Medi

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IR‐783 is a kind of heptamethine cyanine dye that exhibits imaging, cancer targeting and anticancer properties. A previous study reported that its imaging and targeting properties were related to mitochondria. However, the molecular mechanism behind the anticancer activity of IR‐783 has not been well demonstrated. In this study, we showed that IR‐783 inhibits cell viability and induces mitochondrial apoptosis in human breast cancer cells. Exposure of MDA‐MB‐231 cells to IR‐783 resulted in the loss of mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) depletion, mitochondrial permeability transition pore (mPTP) opening and cytochrome c (Cyto C) release. Furthermore, we found that IR‐783 induced dynamin‐related protein 1 (Drp1) translocation from the cytosol to the mitochondria, increased the expression of mitochondrial fission proteins mitochondrial fission factor (MFF) and fission‐1 (Fis1), and decreased the expression of mitochondrial fusion proteins mitofusin1 (Mfn1) and optic atrophy 1 (OPA1). Moreover, knockdown of Drp1 markedly blocked IR‐783‐mediated mitochondrial fission, loss of MMP, ATP depletion, mPTP opening and apoptosis. Our in vivo study confirmed that IR‐783 markedly inhibited tumour growth and induced apoptosis in an MDA‐MB‐231 xenograft model in association with the mitochondrial translocation of Drp1. Taken together, these findings suggest that IR‐783 induces apoptosis in human breast cancer cells by increasing Drp1‐mediated mitochondrial fission. Our study uncovered the molecular mechanism of the anti‐breast cancer effects of IR‐783 and provided novel perspectives for the application of IR‐783 in the treatment of breast cancer.

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Section: Introductionmentioning

confidence: 99%

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Tang

Liu

Zhang

et al. 2018

J Cellular Molecular Medi

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“…Patients with high levels of Beclin-1 presented good prognosis and longer survival (131, 135), and ATG10 downregulation was associated with cell migration and invasion of CRC cells (137). In addition, several compounds were recently demonstrated to suppress colorectal carcinogenesis through the induction of autophagy, including Salvianolic acid B and IR-58 (138, 139). Those findings indicate that promoting autophagy may probably provide an effective strategy for the treatment of CRC.…”

Section: The Roles Of Autophagy In Ibdmentioning

confidence: 99%

Intestinal Autophagy and Its Pharmacological Control in Inflammatory Bowel Disease

Peng

Shao

et al. 2017

Front. Immunol.

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Intestinal mucosal barrier, mainly composed of the intestinal mucus layer and the epithelium, plays a critical role in nutrient absorption as well as protection from pathogenic microorganisms. It is widely acknowledged that the damage of intestinal mucosal barrier or the disturbance of microorganism balance in the intestinal tract contributes greatly to the pathogenesis and progression of inflammatory bowel disease (IBD), which mainly includes Crohn’s disease and ulcerative colitis. Autophagy is an evolutionarily conserved catabolic process that involves degradation of protein aggregates and damaged organelles for recycling. The roles of autophagy in the pathogenesis and progression of IBD have been increasingly studied. This present review mainly describes the roles of autophagy of Paneth cells, macrophages, and goblet cells in IBD, and finally, several potential therapeutic strategies for IBD taking advantage of autophagy.

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“…And this kind of NIR heptamethine dyes is proved to possess structure‐inherent cancer‐specific accumulation property, which is mediated through the organic anion‐transporting polypeptide (OATP) cellular membrane transporters . More importantly, some of these dyes have been demonstrated to target mitochondria and modulate intracellular oxidative state to enhance cell survival, or to induce therapeutic autophagy for colorectal cancer treatment, which provide the possibilities to develop ER stress inducer by targeting mitochondrial functions. In this study, we have synthesized a series of new NIR fluorescent dyes functioned with ester or amino acid groups on the mitochondria‐targeted heptamethine core, and identified NIR fluorophore that induced therapeutic ER stress in cancer cells.…”

mentioning

confidence: 99%

An NIR‐Fluorophore‐Based Therapeutic Endoplasmic Reticulum Stress Inducer

et al. 2018

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The endoplasmic reticulum (ER) stress signaling or unfolded protein response (UPR) is a common feature of many human diseases, including cancer. Excessive activation of ER stress directly induces cell death, holding a new promising strategy for the therapeutic intervention of cancer. Current ER-stress-inducing agents mainly target UPR components or proteasomes, which exert limited treatment efficacy and undesired side effects due to unselective ER stress and poor tumor-specific distribution. In this study, a unique near-infrared (NIR) fluorophore, IR-34, is synthesized and identified to selectively and efficiently trigger tumoricidal ER stress by targeting the mitochondrial protein NDUFS1. IR-34 is demonstrated to specifically accumulate in living cancer cells for tumor NIR imaging and drastically inhibit tumor growth and recurrence without causing apparent toxicity. Thus, this multifunctional NIR fluorophore may represent a novel theranostic agent for tumor imaging-guided treatment and also strengthens the idea that mitochondria could be a useful target for therapeutic ER stress in cancer cells.

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Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44

Cited by 52 publications

References 41 publications

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Intestinal Autophagy and Its Pharmacological Control in Inflammatory Bowel Disease

An NIR‐Fluorophore‐Based Therapeutic Endoplasmic Reticulum Stress Inducer

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