Efficacy of Calreticulin of the Unfolded Protein Response as a Drug Target in HNSCC
Introduction: HNSCC has emerged as one of the major chemo-resistant and aggressive cancer subtypes4. Among prevalent cancers, it has one of the lower 5-year survival probabilities at less than 50%5. While the molecular mechanism behind treatment-resistant HNSCC has been revealed, the clinical applications of the research remains in its early stages5. Tumor cells, especially HNSCC, display high levels of Unfolded Protein Response (UPR) activation as a result of metabolic stress and accumulated unfolded proteins1. The UPR has various anti-apoptotic effects that may contribute to chemoresistance3. The aim of this review was to investigate the role of calreticulin (CRT), an endoplasmic reticulum-resident protein involved in the Unfolded Protein Response (UPR), as a potential drug target in resistant cancers. Materials and methods: The focus of this current work is to review pertinent literature and explore the mechanism of CRT as a contributor of chemoresistance and aggressive metastasis of head and neck (HNSCC). Care was taken to review articles from reputable journals that were both relevant and submitted within the last 5 years. Samples of tumor OSCC cell lines and normal human oral keratinocytes (NHOKs) were used to elucidate the expression of CRT via Western blotting and immunohistochemistry1. Later, shRNA-mediated knockdown of CRT in OSCC cells was generated to analyze cell cycle progression and cell migration in vitro1. Results: CRT was markedly upregulated expressed in OSCC cell lines but not in adjacent NHOKs1. HNSCC cell lines with high levels of CRT showed increased metastasis via increased levels of Focal Adhesion Kinase and Matrix Metalloproteinases1. shRNA-mediated knockdown of CRT in oral cancer cells resulted in significantly reduced growth rate and colony-forming capacity1. This may result from the induction of G0/G1 cell cycle arrest when CRT was depleted in cancer cells. Finally, several drug therapies exist to target CRT, including Ceapins and Kaempferol2. Both have shown clinical promise in colorectal cancer by downregulating CRT and inducing tumor apoptosis in previously resistant cell lines3. Conclusion: Together, this review has evaluated the role of CRT in promoting treatment resistant HNSCC. CRT is a potential drug therapy and may contribute to the malignant phenotype of HNSCC cells.
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- Pluquet, O., & Galmiche, A. (2019). Impact and Relevance of the Unfolded Protein Response in HNSCC. International Journal of Molecular Sciences, 20(11), 2654