Triazoloacridone C-1305 impairs XBP1 splicing by acting as a potential IRE1\u03b1 endoribonuclease inhibitor

Sylwia Bartoszewska,Aneta Pogorzelska,James F Collawn,Maciej Bagiński,Rafal Bartoszewski,David K Crossman,Jarosław Króliczewski

doi:10.1186/s11658-021-00255-y

Abstract

Inositol requiring enzyme 1 alpha (IRE1α) is one of three signaling sensors in the unfolding protein response (UPR) that alleviates endoplasmic reticulum (ER) stress in cells and functions to promote cell survival. During conditions of irrevocable stress, proapoptotic gene expression is induced to promote cell death. One of the three signaling stressors, IRE1α is an serine/threonine-protein kinase/endoribonuclease (RNase) that promotes nonconventional splicing of XBP1 mRNA that is translated to spliced XBP1 (XBP1s), an active prosurvival transcription factor. Interestingly, elevated IRE1α and XBP1s are both associated with poor cancer survival and drug resistance. In this study, we used next-generation sequencing analyses to demonstrate that triazoloacridone C-1305, a microtubule stabilizing agent that also has topoisomerase II inhibitory activity, dramatically decreases XBP1s mRNA levels and protein production during ER stress conditions, suggesting that C-1305 does this by decreasing IRE1α’s endonuclease activity.

Highlights

During tumor development and progression, transformed cells adapt to increased demands on protein and lipid production that are needed for rapid proliferation [1] by enhancing endoplasmic reticulum (ER) function and expansion
In examining the effects of C-1305 on the active isoform of X-box binding protein 1 (XBP1), XBP1s, the results indicated that the levels of this mRNA were dramatically lower in all three cell lines (Fig. 2c) which was surprising given that the ERN1 mRNA levels were increased
Despite the fact that Inositol-requiring protein 1 alpha (IRE1α)’s molecular activities are mostly related to facilitating cellular survival, during irrevocable ER stress, this enzyme can contribute to accumulation of proinflammatory and apoptotic factors [52]

Summary

Introduction

During tumor development and progression, transformed cells adapt to increased demands on protein and lipid production that are needed for rapid proliferation [1] by enhancing endoplasmic reticulum (ER) function and expansion. Cancer cells take advantage of the adaptive multifunctional signaling pathway called the unfolded protein response (UPR) [1]. The normal function of this pathway is to protect cells against the accumulation of unfolded or misfolded proteins in ER. The UPR does this by activating three ER transmembrane sensors: inositol-requiring protein 1 alpha (IRE1α encoded by ERN1), protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6 (ATF6) [2]. The function of the UPR is to promote cell survival and restore proper ER function, or alternatively during irrevocable stress, to trigger cell death when cellular homeostasis cannot be restored [3].

Methods

Results

Conclusion