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Targeting Perk and Grp78 in Colorectal Cancer: Genetic Insights and Novel Therapeutic Approaches Publisher Pubmed



Mafi S1 ; Dehghani M2 ; Khalvati B3 ; Abidi H1 ; Ghorbani M4 ; Jalali P5 ; Whichelo R6 ; Salehi Z7 ; Markowska A8 ; Reyes A9 ; Pecic S9 ; Los MJ10, 11 ; Ghavami S12, 13, 14 ; Nikseresht M1
Authors
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Authors Affiliations
  1. 1. Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
  2. 2. Hematology and Medical Oncology Department, Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  3. 3. Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
  4. 4. Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
  5. 5. Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  6. 6. College of Biological Science, University of Guelph, Guelph, N1G 2W1, ON, Canada
  7. 7. Hematology, Oncology and Stem Cell Transplantation Research Center, Research Institute for Oncology, Hematology and Cell Therapy, Tehran University of Medical Sciences, Tehran, Iran
  8. 8. Faculty of Health Sciences, Medical University of Warsaw, Warsaw, 03-242, Poland
  9. 9. Department of Chemistry and Biochemistry, California State University, Fullerton, 92834, CA, United States
  10. 10. Biotechnology Center, Silesian University of Technology, Gliwice, Poland
  11. 11. Linkocare LifeSciences AB, Linkoping, Sweden
  12. 12. Faculty of Medicine, Rolna 43, Katowice, Poland
  13. 13. Paul Albrechtsen Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada
  14. 14. Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

Source: European Journal of Pharmacology Published:2024


Abstract

Colorectal cancer (CRC) ranks among the leading causes of cancer-related deaths worldwide. Enhancing CRC diagnosis and prognosis requires the development of improved biomarkers and therapeutic targets. Emerging evidence suggests that the unfolded protein response (UPR) plays a pivotal role in CRC progression, presenting new opportunities for diagnosis, treatment, and prevention. This study hypothesizes that genetic variants in endoplasmic reticulum (ER) stress response genes influence CRC susceptibility. We examined the frequencies of SNPs in PERK (rs13045) and GRP78/BiP (rs430397) within a South Iranian cohort. We mapped the cellular and molecular features of PERK and GRP78 genes in colorectal cancer, observing their differential expressions in tumor and metastatic tissues. We constructed co-expression and protein-protein interaction networks and performed gene set enrichment analysis, highlighting autophagy as a significant pathway through KEGG. Furthermore, the study included 64 CRC patients and 60 control subjects. DNA extraction and genotyping were conducted using high-resolution melting (HRM) analysis. Significant differences in PERK and GRP78 expressions were observed between CRC tissues and controls. Variations in PERK and GRP78 genotypes were significantly correlated with CRC risk. Utilizing a Multi-Target Directed Ligands approach, a dual PERK/GRP78 inhibitor was designed and subjected to molecular modeling studies. Docking experiments indicated high-affinity binding between the proposed inhibitor and both genes, PERK and GRP78, suggesting a novel therapy for CRC. These findings highlight the importance of understanding genetic backgrounds in different populations to assess CRC risk. Polymorphisms in UPR signaling pathway elements may serve as potential markers for predicting CRC susceptibility, paving the way for personalized therapeutic strategies. © 2024 The Authors
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