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

Abstract

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.

DRP1 upregulation promotes pancreatic cancer growth and metastasis through increased aerobic glycolysis

“…During recent years, a growing body of evidence has suggested the close links between mitochondrial fission and fusion dysfunction and cancers . Dysregulated expressions of DRP1 and DRP1 and MFN2 have been observed in several types of cancer such as liver, breast, and lung cancers. However, the expression patterns and biological effects of these mitochondrial fission and fusion regulators in PC remain largely unknown.…”

Mitochondrial division inhibitor (mdivi-1) decreases oxidative metabolism in cancer

“…15,16 Mitochondrial fusion and fission contribute to these morphologic changes and are often dysregulated under pathological conditions, including cancers. 18,19,25,28,51 Most studies of cancer-related mitochondrial dynamics focus on their function in apoptosis, [52][53][54] and elevated mitochondrial fission has been linked to impaired oxygen consumption in cancer cells. 18,[55][56][57] However, it is not clear whether mitochondrial dynamics regulate metabolic alterations in cancer.…”

“…25 High expression of DRP1 in cancer may be a potential target for cancer treatment. 4,5,22,24,[26][27][28] Mitochondrial division inhibitor 1 (mdivi-1) is an efficacious inhibitor of mitochondrial division in yeast and was identified from a chemical screen for compounds that alter mitochondrial morphology. 29 Not surprisingly, mdivi-1 has been widely used as a mitochondrial fusion inducer.…”

Targeted OMA1 therapies for cancer

“…85 Also cryptolepine and IR-783 inhibited tumor cell growth and at the same time led to dose-dependent OPA1 protein loss. 251,252 Accordingly, rat neuroblastoma cells after cisplatin treatment and successive long-term recovery showed increased OPA1 protein levels and more fused mitochondria. 253 Another study demonstrated p53-dependent OPA1 cleavage in cisplatin treated human cervical and ovarian cancer cell lines, 169 which suggests that chemotherapies exert their cytotoxic effects through OMA1mediated OPA1 cleavage in a p53-dependent manner.…”

“…For example, one study found that sorafenib induced rapid mitochondrial fragmentation, cytochrome c release and apoptosis in hepatocellular carcinoma cells, which involved loss of OPA1 and which was further amplified by OPA1 knock‐down . Also cryptolepine and IR‐783 inhibited tumor cell growth and at the same time led to dose‐dependent OPA1 protein loss . Accordingly, rat neuroblastoma cells after cisplatin treatment and successive long‐term recovery showed increased OPA1 protein levels and more fused mitochondria .…”