PERK-Olating Through Cancer - A Brew of Cellular Decisions

Sep 23, 2026

Uploaded by Noah

PERK is an endoplasmic reticulum (ER) transmembrane kinase with a multifaceted role in cancer development, progression, and stress signaling. Activation of PERK is one arm of the unfolded protein response (UPR) triggered by ER stress in tumor cells, often producing either pro-survival or proapoptotic effects depending on context and stress intensity. PERK supports survival under oncogenic and microenvironmental pressures while also contributing to tumor initiation, adaptation, and chemoresistance. Prolonged PERK activation can instead impair proliferation and promote apoptosis through interconnected mechanisms including mitochondrial dysfunction, translational inhibition, stress accumulation, and induction of proapoptotic factors such as CHOP, making PERK a complex therapeutic target.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages33

Reading Time1 h 23 min

AccessFree to download

Introduction

PERK and ER stress in cancer

UPR sensors and signaling pathways

Review PERK-Olating Through Cancer: A Brew of Cellular Decisions Laurent Mazzolini *,† and Christian Touriol *,† Academic Editor: Piero Crespo Received: 20 December 2024 Revised: 24 January 2025 Accepted: 5 February 2025 Published: 8 February 2025 Citation: Mazzolini, L.; Touriol, C. PERK-Olating Through Cancer: A Brew of Cellular Decisions. Biomolecules 2025, 15, 248. [https://](https://)[ ](https://)[doi.org/10.3390/biom15020248](doi.org/10.3390/biom15020248) [Copyright:](Copyright:) © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) . Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR-1037, CNRS UMR-5071, Université de Toulouse, Avenue Hubert Curien, Oncopole Entrée C, CS 53717, 31037 Toulouse CEDEX 1, France * Correspondence: [laurent.mazzolini@inserm.fr](laurent.mazzolini@inserm.fr) (L.M.); [christian.touriol@inserm.fr](christian.touriol@inserm.fr) (C.T.) † These authors contributed equally to this work. Abstract: The type I protein kinase PERK is an endoplasmic reticulum (ER) transmembrane protein that plays a multifaceted role in cancer development and progression, inﬂuencing tumor growth, metastasis, and cellular stress responses. The activation of PERK represents one of the three signaling pathways induced during the unfolded protein response (UPR), which is triggered, in particular, in tumor cells that constitutively experience various intracellular and extracellular stresses that impair protein folding within the ER. PERK activation can lead to both pro-survival and proapoptotic outcomes, depending on the cellular context and the extent of ER stress. It helps the reprogramming of the gene expression in cancer cells, thereby ensuring survival in the face of oncogenic stress, such as replicative stress and DNA damage, and also microenvironmental challenges, including hypoxia, angiogenesis, and metastasis. Consequently, PERK contributes to tumor initiation, transformation, adaptation to the microenvironment, and chemoresistance. However, sustained PERK activation in cells can also impair cell proliferation and promote apoptotic death by various interconnected processes, including mitochondrial dysfunction, translational inhibition, the accumulation of various cellular stresses, and the speciﬁc induction of multifunctional proapoptotic factors, such as CHOP. The dual role of PERK in promoting both tumor progression and suppression makes it a complex target for therapeutic interventions. A comprehensive understanding of the intricacies of PERK pathway activation and their impact is essential for the development of effective therapeutic strategies, particularly in diseases like cancer, where the ER stress response is deregulated in most, if not all, of the solid and liquid tumors. This article provides an overview of the knowledge acquired from the study of animal models of cancer and tumor cell lines cultured in vitro on PERK's intracellular functions and their impact on cancer cells and their microenvironment, thus highlighting potential new therapeutic avenues that could target this protein. Keywords: PERK; unfolded protein response (UPR); ER stress; cancer; microenvironment; resistance; cell death 1. Introduction As neoplastic cells proliferate, they encounter numerous stresses to which they must adapt in order to survive. In the context of the whole organism, cells must acquire the capacity to evade detection and destruction by the immune system, as well as to escape the growth inhibitory signals sometimes originating from surrounding cells [1,2] . Furthermore, the harsh growth conditions experienced by tumor cells due to deﬁcits in the nutrient and oxygen supply resulting from insufﬁcient blood ﬂow w

FAQs

What is PERK and where does it act in the cell?

PERK is a transmembrane kinase located in the endoplasmic reticulum (ER). It participates in signaling that responds to ER stress in cancer cells.

How is PERK activation connected to the unfolded protein response (UPR)?

PERK activation is one of the three signaling pathways induced during the UPR. The UPR is triggered when tumor cells experience intracellular and extracellular stresses that disrupt protein folding in the ER.

Why can PERK both promote tumor progression and trigger apoptosis?

PERK can yield pro-survival or proapoptotic outcomes depending on cellular context and the extent of ER stress. Sustained PERK activation can impair proliferation and promote apoptosis through mechanisms such as translational inhibition and stress accumulation, including CHOP induction.

Sep 23, 2026

Uploaded by Noah