erastin and Colorectal-Neoplasms

Colorectal cancer (CRC) is the leading cause of cancer associated death worldwide. Ferroptosis is a newly defined form of regulated cell death characterized by the accumulation of lipid hydroperoxides and exerts an increased attention for cancer treatment. However, little is known about ferroptosis in CRC. In this study, through whole genome sequencing and external differential differentiated expression analysis, we identify CUL9 as a novel important modulator for ferroptosis in CRC. Here we demonstrated that CUL9 can binds p53 to ubiquitylate heterogeneous nuclear ribonucleoprotein C for degradation. Overexpression of CUL9 increases resistance to erastin-induced ferroptosis. Then, we discovered this resistance was mediated by CUL9-HNRNPC-MATE1 negative loop, which can provide us with a novel target to overcome drug resistance to ferroptosis activators. Finally, we found that targeting MDM2 was developed as an effective strategy to destroy precious drug-resistant CRC cells.

Topics: Colorectal Neoplasms; Cullin Proteins; Ferroptosis; Heterogeneous-Nuclear Ribonucleoprotein Group C; Humans; Piperazines; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53

In this study, we examined whether and how miR-545 modulates ferroptosis in colorectal cancer (CRC). HT-29 and HCT-116 human CRC cell viability was examined using a CCK-8 assay and malondialdehyde (MDA) and Fe

Topics: Animals; Cell Survival; Colorectal Neoplasms; Ferroptosis; HCT116 Cells; Humans; Mice; Mice, Nude; MicroRNAs; Piperazines; Reactive Oxygen Species; Signal Transduction

Ferroptosis, a newly iron-dependent form of cell death, is often accompanied by the damage of membrane lipid peroxide. Recently, the ferroptosis inducer erastin has been reported to exhibit potential anti-cancer activities. The aim of this study was to investigate the effects of SRSF9 on the sensitivity of colorectal cancer (CRC) to erastin and explore the underlying molecular mechanism. Short hairpin RNAs (shRNAs) or SRSF9 overexpression vector (SRSF9-OE) was transfected into erastin-induced human CRC cells to inhibit or overexpress SRSF9. Results showed that SRSF9 inhibition promoted the cell death induced by erastin, conversely, SRSF9 overexpression augmented the resistance to erastin-induced death in human CRC cells. SRSF9 decreased lipid peroxide damage which was a key event during erastin-induced ferroptosis in human CRC cells. Furthermore, we found that SRSF9 inhibition increased erastin-induced ferroptosis by downregulating GPX4 level. In an In vivo study, SRSF9 shRNA or SRSF9-OE stably transfected human CRC cells were subcutaneously injected into the right flank of nude mice. SRSF9 overexpression partly abolished the tumor growth inhibition and ferroptosis induced by erastin. Our data indicated SRSF9's regulation of GPX4 as an essential mechanism driving CRC tumorigenesis and resistance of erastin-induced ferroptosis. This molecular mechanism may provide a novel method for improving the sensitivity of CRC to erastin.

Topics: Animals; Caco-2 Cells; Cell Death; Cell Line, Tumor; Colorectal Neoplasms; Ferroptosis; HCT116 Cells; Humans; Iron; Lipid Peroxidation; Male; Mice; Mice, Nude; Phospholipid Hydroperoxide Glutathione Peroxidase; Piperazines; Reactive Oxygen Species; RNA, Small Interfering; Serine-Arginine Splicing Factors; Xenograft Model Antitumor Assays

Topics: Apoptosis; Cell Survival; Colorectal Neoplasms; Ferroptosis; HCT116 Cells; Heme Oxygenase-1; Humans; NF-E2-Related Factor 2; Piperazines; Sesquiterpenes; Signal Transduction

Ferroptosis is a new mode of regulated cell death, which is completely distinct from other cell death modes based on morphological, biochemical, and genetic criteria. This study evaluated the therapeutic role of ferroptosis in classic chemotherapy drugs, including the underlying mechanism.. Cell viabilitywas detected by using the methylthiazoltetrazlium dye uptake method. RNAiwas used to knockout iron-responsive element binding protein 2, and polymerase chain reaction, western blot was used to evaluate the efficiency. Intracellular reduced glutathione level and glutathione peroxidases activitywere determined by related assay kit. Intracellularreactive oxygen species levelswere determined by flowcytometry. Electron microscopywas used to observe ultrastructure changes in cell.. Among five chemotherapeutic drugs screened in this study, cisplatin was found to be an inducer for both ferroptosis and apoptosis in A549 and HCT116 cells. The depletion of reduced glutathione caused by cisplatin and the inactivation of glutathione peroxidase played the vital role in the underlying mechanism. Besides, combination therapy of cisplatin and erastin showed significant synergistic effect on their anti-tumor activity.. Ferroptosis had great potential to become a new approach in anti-tumor therapies and make up for some classic drugs, which open up a new way for their utility in clinic.

Topics: A549 Cells; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Death; Cisplatin; Colorectal Neoplasms; Fibrosarcoma; Glutathione Peroxidase; HCT116 Cells; Humans; Lung Neoplasms; Neoplasms; Piperazines

Ferroptosis is a form of regulated cell death that may facilitate the selective elimination of tumor cells. The tumor suppressor p53 (TP53) has been demonstrated to promote ferroptosis via a transcription-dependent mechanism. Here, we show that TP53 limits erastin-induced ferroptosis by blocking dipeptidyl-peptidase-4 (DPP4) activity in a transcription-independent manner. Loss of TP53 prevents nuclear accumulation of DPP4 and thus facilitates plasma-membrane-associated DPP4-dependent lipid peroxidation, which finally results in ferroptosis. These findings reveal a direct molecular link between TP53 and DPP4 in the control of lipid metabolism and may provide a precision medicine strategy for the treatment of colorectal cancer by induction of ferroptosis.

Topics: Adamantane; Animals; Antineoplastic Agents; Apoptosis; Caco-2 Cells; Cell Line, Tumor; Cell Membrane; Cell Nucleus; Colorectal Neoplasms; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Injections, Subcutaneous; Iron; Lipid Peroxidation; Mice; Mice, Nude; Nitriles; Piperazines; Pyrrolidines; RNA, Small Interfering; Signal Transduction; Tumor Suppressor Protein p53; Vildagliptin; Xenograft Model Antitumor Assays

We here evaluated the potential anti-colorectal cancer activity by erastin, a voltage-dependent anion channel (VDAC)-binding compound. Our in vitro studies showed that erastin exerted potent cytotoxic effects against multiple human colorectal cancer cell lines, possibly via inducing oxidative stress and caspase-9 dependent cell apoptosis. Further, mitochondrial permeability transition pore (mPTP) opening was observed in erastin-treated cancer cells, which was evidenced by VDAC-1 and cyclophilin-D (Cyp-D) association, mitochondrial depolarization, and cytochrome C release. Caspase inhibitors, the ROS scavenger MnTBAP, and mPTP blockers (sanglifehrin A, cyclosporin A and bongkrekic acid), as well as shRNA-mediated knockdown of VDAC-1, all significantly attenuated erastin-induced cytotoxicity and apoptosis in colorectal cancer cells. On the other hand, over-expression of VDAC-1 augmented erastin-induced ROS production, mPTP opening, and colorectal cancer cell apoptosis. In vivo studies showed that intraperitoneal injection of erastin at well-tolerated doses dramatically inhibited HT-29 xenograft growth in severe combined immunodeficient (SCID) mice. Together, these results demonstrate that erastin is cytotoxic and pro-apoptotic to colorectal cancer cells. Erastin may be further investigated as a novel anti-colorectal cancer agent.

Topics: Animals; Apoptosis; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; HT29 Cells; Humans; Mice, SCID; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Piperazines; Reactive Oxygen Species; Voltage-Dependent Anion Channel 1; Xenograft Model Antitumor Assays