Importance of PERK pathway modulation on colorectal cancer management: a systematic review

Abstract

Background: The protein kinase RNA-like endoplasmic reticulum kinase (PERK) branch of the Unfolded Protein Response (UPR) plays a complex and context-dependent role in the colorectal cancer (CRC). While some studies indicate that PERK activation suppresses tumor growth by inducing apoptosis and limiting proliferation, others suggest that it may promote tumor progression by supporting cancer cell survival under stress. This systematic review aims to clarify the dual role of PERK signaling in CRC and evaluate its potential as a therapeutic target. Methods: We included full-text English-language studies investigating the role of PERK signaling in CRC using in vitro and/or animal models. Studies on non-CRC malignancies or unrelated mechanisms were excluded. Searches were conducted in PubMed, Web of Science (WOS), and Scopus using relevant keywords. Results: A total of 395 articles were initially identified. After removing duplicates (n = 173), review articles (n = 11), and unrelated studies (n = 66), 45 studies met the inclusion criteria. Most of these (n = 36) used in vitro models, with the HCT-116 cell line being the most frequently used (n = 19). While most studies (n = 36) reported anti-tumorigenic effects associated with PERK activation, several identified conditions under which PERK signaling may support tumor progression. These conflicting findings may be attributed to differences in experimental models, PERK modulation strategies, and endoplasmic reticulum stress induction methods. Conclusions: This review highlights the dual and context-dependent nature of PERK pathway activation in CRC. Although PERK often appears to exert tumor-suppressive effects, evidence also points to its tumor-promoting potential under certain conditions. A nuanced understanding of these roles is crucial for developing PERK-targeted therapies in CRC. Trial registration: This systematic review has been registered in PROSPERO (International Prospective Register of Systematic Reviews) with the registration number CRD42023241342.