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Autophagy orchestrates anti-tumor immunity to enhance chemo-sensitivity by upregulation of TIMP-2 through FBXW2/CEBPB axis in Colorectal Cancer

ABSTRACT: 5-FU based chemotherapy remains one of the mainstay strategies for treating patients with colon rectal cancer (CRC). However, molecular properties determining response to chemotherapy are still elusive. Here, we demonstrated that efficacy of 5-FU and Oxaplatin treatment(5-FU/Oxa) requires tumor-cell intrinsic autophagy, particularly fostering a tumor-suppressive microenvironment with an augmented presence of total and active CD8+ T cell populations. Inhibition of autophagy significantly reduced intra-tumoral abundance of CD8+T cells, thus impeding the efficacy of 5-FU/Oxa. Autophagy-deficient tumor cells exhibited remarkably less production of TIMP-2, a secreted endogenous MMP2/9 inhibitor, upon exposure to 5-FU/Oxa. Knockout of TIMP-2 in tumor cells mimicked the effect of autophagy inhibition, whereas overexpression of TIMP-2 or co-administration of MMP-2/9 inhibitor in autophagy-defective tumor cells successfully restored the efficacy of 5-FU/Oxa treatment which depended on CD8+T cells. Mechanistically, autophagy-mediated degradation of FBXW2 triggered by 5-FU/Oxa treatment reciprocally led to accumulation of CEBPB, therefore responsible for transcriptional upregulation of TIMP-2. Clinically, autophagy displayed strongly positive correlation with TIMP-2 expression. Patients responded better to 5-FU based chemotherapy possessed higher autophagy status and TIMP-2 expression. Collectively, our study unraveled a novel role of tumor-cell intrinsic autophagy in modulating tumor immune microenvironment (TIME), thus contributing to chemotherapeutic sensitivity in CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309895 | GEO | 2026/09/18

REPOSITORIES: GEO

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Project description:Purpose: 5-FU resistance is considered to be a possible reason for the failure of conventional drug treatment of colorectal cancer (CRC). Recently, salinomycin (SAL), as a selective inhibitor of cancer stem cells (CSCs), has been used to sensitize and attenuate a variety of solid tumor chemotherapy drugs. In our study, our goal was to combine SAL with 5-FU to explore whether increase the sensitivity of CRC to 5-FU and the molecular mechanism that involved in enhancing 5-FU sensitivity and promoting tumor cell chemotherapeutic death. Methods: ComboSyn software was used to study whether dual drug combinations synergistically promote each other and their dosage. CCK8, EdU and Annexin V/PI assays were used to study the cell proliferation and apoptosis of SW480 and HCT116 cells in response to SAL single-drug and dual-drug co-treatment. Cell cycle staining was used to assess cycle arrest. Wound healing and migration and invasion experiments were used to identify changes in migration and invasion capabilities under the influence of different drugs. Transcriptome sequencing is used to explore the molecular mechanisms of drugs. ROS fluorescence staining and MDA level measurement were used to confirm the changes in ferroptosis levels of SW480 and HCT116 cells after drug treatment. Nude xenograft mice were used to detect antitumor in vivo. Changes in the protein level expression of ferroptosis GPX4 and SLC7A11 were also determined in the treated cells.Results: SAL alone and combination of 5-FU were found to significantly increase cell mortality and apoptosis. At the same time, our results show that the blending of SAL and 5-FU not only inhibits the proliferation, migration, and invasion of CRC colorectal cancer cell lines in vivo and in vitro, but also promotes ferroptosis of CRC cell lines by downregulating the expression of GPX4 and SLC7A11. It may provide more and novel solutions and treatment perspectives for 5-FU or other drug-resistant chemotherapy strategies for CRC patients.Conclusions: SAL inhibiting colorectal cancer whose effect is achieved by reducing GPX4 and SLC7A11 protein levels to mediate ferroptosis activation in collaboration with 5-fluorouracil.

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Autophagy orchestrates anti-tumor immunity to enhance chemo-sensitivity by upregulation of TIMP-2 through FBXW2/CEBPB axis in Colorectal Cancer

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