PRAS40 activates the IRE1α-XBP-1-mediated unfolded protein response to exacerbate colorectal cancer by enhancing ST6Gal1-dependent α-2, 6 sialylation of GRP78

Sep 23, 2026

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Colorectal cancer (CRC) progression could be fueled by activation of the unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress. PRAS40 is linked to cancer progression, yet its UPR role remained unclear. This study shows PRAS40 promotes the IRE1α-XBP1 axis-dependent UPR to drive CRC progression. Mechanistically, PRAS40 interacts with GRP78 and boosts its N-glycosylation, enhancing GRP78-ST6Gal1 binding and α-2,6-sialylation, while β-sitosterol inhibits ST6Gal1 to attenuate PRAS40-triggered tumor growth, nominating ST6Gal1 as a therapeutic target.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

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Introduction

Unfolded protein response and ER stress in CRC

GRP78 as a therapeutic target and regulation mechanisms

PRAS40 in oncogenic signaling and the research gap

Results

PRAS40 promotes IRE1α-XBP1-mediated UPR during CRC progression

PRAS40-GRP78 interaction and enhanced GRP78 N-glycosylation

ST6Gal1-dependent α-2,6-sialylation of GRP78

β-sitosterol as an ST6Gal1 inhibitor and tumor growth attenuation

Neoplasia 75 (2026) 101297 Contents lists available at ScienceDirect Neoplasia journal [homepage:](homepage: www.elsevier.com/locate/neo)[ www.elsevier.com/locate/neo](homepage: www.elsevier.com/locate/neo) | Original Research
PRAS40 activates the IRE1α-XBP-1-mediated unfolded protein response to exacerbate colorectal cancer by enhancing ST6Gal1-dependent α-2, 6 sialylation of GRP78 | | | | | --- | --- | --- | --- | | Hongming Tenga,b,1, Yuxin Guo a,1, Xinran Chena, Anlian Fan a, Chengfei Zhang a, Ting Zhang a,b, Yuanyuan Luo a,b, Lin Huang a,b,*
a Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, 9 South Lvshun Road, Dalian, Liaoning 116044, PR China b Liaoning Provincial Key Laboratory of Medical Cellular and Molecular Biology, 9 South Lvshun Road, Dalian, Liaoning 116044, PR China | | | | | A R T I C L E I N F O | | A B S T R A C T | | | Keywords:
Colorectal cancer The unfolded protein response Endoplasmic reticulum stress GRP78
PRAS40 | | Colorectal cancer (CRC) progression could be fueled by the activation of the unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress. The proline-rich Akt1 substrate of 40 kDa (PRAS40) is implicated in cancer progression, but its role in the UPR remains unclear. Herein, we demonstrate that PRAS40 promotes the inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) axis-dependent UPR in driving CRC progression. Mechanistically, PRAS40 interacts with ER chaperone glucose-regulated protein 78 (GRP78) and enhances its N-glycosylation. Moreover, PRAS40 improves the interaction between GRP78 and ST6 β-galactoside α-2, 6-sialyltransferase 1 (ST6Gal1), leading to increased α-2, 6-sialylation of GRP78 and the UPR triggered by ER stress. Furthermore, we identified the natural compound β-sitosterol as a novel ST6Gal1 inhibitor, which attenuated PRAS40-triggered tumor growth. Collectively, these findings unveil a PRAS40-ST6Gal1-GRP78 axis that drives CRC progression through activating the IRE1α-XBP-1-mediated UPR and nominate ST6Gal1 as a promising therapeutic target. | | Introduction Colorectal cancer (CRC) remains a leading cause of global cancerrelated morbidity and mortality, with clinical management persistently challenged by late-stage diagnosis, metastatic progression, and therapeutic resistance [1,2]. A pivotal mechanism underlying these challenges is the activation of the unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress. Within the hostile tumor microenvironment characterized by hypoxia, nutrient deprivation, and acidosis, cancer cells frequently experience ER stress [3–5]. Sensing this stress, the molecular chaperone glucose-regulated protein 78 (GRP78) initiates the UPR by dissociating from inositol-requiring enzyme 1α(IRE1α), PKR-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6), and sequentially activates the IRE1α-XBP1, PERK-eIF2α-ATF4, and ATF6 signaling pathways to enhance cell survival, metabolic reprogramming, immunomodulation, and oxidative stress mitigation. Consequently, the UPR transforms a potentially lethal cellular state into a powerful engine for cancer progression and treatment resistance [3–6]. GRP78 is frequently overexpressed in solid tumors, where its elevated levels are associated with enhanced cell proliferation, invasion, and poor clinical prognosis across multiple cancer types, including CRC [7,8]. Therefore, GRP78 has emerged as a promising therapeutic target, with inhibition strategies demonstrating antitumor potential [9,10]. The expression of GRP78 is transcriptionally upregulated by the key UPR transducers XBP1s, ATF4, and ATF6 [11–13]. Besides transcriptional control, GRP78 function is intricately regulated by various post-translational modifications, such as phosphorylation, acetylation, palmitoylation, AMPylation, and glycosylation, which critically modulate its stability and acti

FAQs

How does ER stress trigger the unfolded protein response relevant to colorectal cancer?

ER stress initiates UPR by GRP78 dissociating from IRE1α, PERK, and ATF6, sequentially activating IRE1α-XBP1, PERK-eIF2α-ATF4, and ATF6 pathways. The resulting UPR supports survival and treatment resistance in cancer cells.

What role does PRAS40 play in the IRE1α-XBP1-mediated UPR during CRC progression?

PRAS40 promotes the IRE1α-XBP1 axis-dependent UPR to drive CRC progression. It binds GRP78 and facilitates GRP78 interaction with ST6Gal1, enhancing α-2,6-sialylation and UPR activation via ER stress.

How was ST6Gal1 targeted, and what was the impact on PRAS40-triggered tumor growth?

The natural compound β-sitosterol was identified as a ST6Gal1 inhibitor. Its use attenuated PRAS40-triggered tumor growth, supporting ST6Gal1 as a promising therapeutic target.

Sep 23, 2026

Uploaded by Rhys