Inhibition of IRE1 RNase activity modulates tumor cell progression and enhances the response to chemotherapy in colorectal cancer

• Published in: Medical oncology (Northwood, London, England) London, England), 2023-07, Vol.40 (9), p.247-247, Article 247
• Main Authors: Abbasi, Sana, Rivand, Helia, Eshaghi, Fatemeh, Moosavi, Mohammad Amin, Amanpour, Saeid, McDermott, Michael F., Rahmati, Marveh
• Format: Article
• Language: English
• Subjects: Chemotherapy; Colorectal cancer; Cytotoxicity; Hematology; Internal Medicine; Medicine; Medicine & Public Health; Oncology; Original Paper; Pathology
• ISSN: 1559-131X; 1357-0560; 1559-131X
• DOI: 10.1007/s12032-023-02105-7

Drug resistance is one of the clinical challenges that limits the effectiveness of chemotherapy. Recent reports suggest that the unfolded protein response (UPR) and endoplasmic reticulum stress-adaptation signalling pathway, along with increased activation of its inositol-requiring enzyme 1α (IRE1α) arm, may be contributors to the pathogenesis of colorectal cancer (CRC). Here, we aimed to target the IRE1α/XBP1 pathway in order to sensitise CRC cells to the effects of chemotherapy. The CT26 colorectal cell line was treated with tunicamycin, and then was exposed to different concentrations of 5-fluorouracil (5-FU), either alone and/or in combination with the IRE1α inhibitor, 4µ8C. An MTT assay, flow cytometry and RT-PCR were performed to determine cell growth, apoptosis and IRE1α activity, respectively. In vivo BALB/c syngeneic colorectal mice received chemotherapeutic drugs. Treatment responses, tumour sizes and cytotoxicity were assessed via a range of pathological tests. 4µ8C was found to inhibit the growth of CRC, at a concentration of 10 µg/ml, without detectable cytotoxic effects and also significantly enhanced the cytotoxic potential of 5-FU, in CRC cells. In vivo experiments revealed that 4µ8C, at a concentration of 50 µM/kg prevented tumour growth without any cytotoxic or metastatic effects. Interestingly, the combination of 4µ8C with 5-FU remarkably enhanced drug responses, up to 40–60% and also lead to significantly greater inhibition of tumour growth, in comparison to monotherapy, in CRC mice. Targeting the IRE1α/XBP1 axis of the UPR could enhance the effectiveness of chemotherapy in both in vitro and in vivo models of CRC.