Up to date: Endoplasmic reticulum stress-targeted colorectal cancer therapy

Year 2025, Volume: 55 Issue: 1, 119 - 130, 07.05.2025

Gülşah Gamze Arcan , Pınar Aksoy Sağırlı

https://doi.org/10.26650/IstanbulJPharm.2025.1574537

Abstract

Colorectal cancer (CRC) is one of the most prevalent cancer types worldwide, and the development of new targets in treatment approaches is of critical importance. In recent years, there has been a growing interest in the role of endoplasmic reticulum (ER) stress in the development of CRC and the effectiveness of cancer treatments. ER stress is a process linked to the disruption of cellular homeostasis and the activation of diverse biochemical pathways. Increased ER stress can influence cell fate by activating either adaptive pathways that promote survival or apoptotic pathways that lead to cell death. Proteins such as X-box binding protein-1 spliced form (XBP-1s), activating transcription factor 4 (ATF4), and activating transcription factor 6 (ATF6) are predominantly implicated in the adaptive response, whereas CCAAT/ enhancer-binding protein (C/EBP) homologous protein (CHOP) and phospho-apoptosis signal regulating kinase 1 (p-ASK1) are primarily associated with the apoptotic response. Nonetheless, the functional roles of these proteins may vary depending on the specific conditions. The purpose of this review is to evaluate studies primarily conducted over the past decade, focusing specifically on the effects of existing drugs and candidate molecules used in CRC treatment on ER stress proteins, emphasising their role in reducing drug resistance and enhancing the efficacy of treatment. Considering the articles reviewed in this compilation, it is concluded that the suppression of the adaptive pathway [inositol requiring enzyme - 1α (IRE-1α)/XBP-1s ] through inhibitors and the prolongation of ER stress to activate apoptotic proteins (CHOP, p-ASK1) can enhance drug efficacy and reverse drug resistance. This approach is considered a novel and effective therapeutic strategy for CRC.

Keywords

Adaptive pathway , Apoptotic pathway , Cancer treatment efficacy , Drug resistance , Endoplasmic reticulum-targeted colorectal cancer therapy , Unfolded protein response

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