Protein misfolding and cancer - proteomics as an approach for biomarker discovery

The unfolded protein response (UPR) refers to a cellular response mechanism that occurs in response to the accumulation of misfolded or incompletely folded proteins in the ER, that maintains proteostasis. While the major aim of UPR is to restrain cell homeostasis, prolonged stages results in apoptosis. The oncogenic circumstances are typically ER stressors, and UPR activation encourages the oncogenic transformation process, in which all UPR signaling branches support the development of tumors, angiogenesis, immune invasion, and resistance to chemotherapy. Proteomics is a high throughput, large-scale comprehensive study of proteins, their structures, and functions including their interactions with each other. Proteomics has now emerged as a very crucial and robust technique for biomarker discovery especially in diseases such as cancer. We summarize the use of proteomics techniques emphasizing the identification of UPR-related biomarkers by enabling the examination of protein-level alterations and modifications that propel UPR-mediated carcinogenesis. This could further be exploited for the early detection, prognosis, diagnosis and for therapeutic interventions for ER stress-mediated and UPR-mediated malignancies. This review elucidates the significant role and importance of different proteomic technologies and strategies in revealing UPR-mediated pathways in cancer, identifying main UPR effectors including GRP78, p53, PERK, IRE1α, and ATF6, and examines their potential as biomarkers for different cancer types. Integrating proteomic data with systems biology and machine learning techniques would further enhance our comprehension of UPR signaling in oncogenesis and facilitate the development of innovative tactics for personalized cancer therapy.