Jay Young

 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.

1. Chiang, W.-F., Hwang, T.-Z., Hour, T.-C., Wang, L.-H., Chiu, C.-C., Chen, H.-R., … Chen, J. Y.-F. (2015). Calreticulin, an endoplasmic reticulum-resident protein, is highly expressed and essential for cell proliferation and migration in oral squamous cell carcinoma. Oral Oncology, 49(6), 534–541. doi: 10.1016/j.oraloncology.2013.01.003
2. Gallagher, C. M., & Walter, P. (2016). Ceapins inhibit ATF6α signaling by selectively preventing transport of ATF6α to the Golgi apparatus during ER stress. ELife, 5.
3. Harada, K., Takenawa, T., Ferdous, T., Kuramitsu, Y., & Ueyama, Y. (2017). Calreticulin is a novel independent prognostic factor for oral squamous cell carcinoma. Oncology Letters, 13(6), 4857–4862. doi: 10.3892/ol.2017.6062
4. Mathew, Maya, and Sufi Mary. “The Cellular Microenvironment of Head and Neck Squamous Cell Carcinoma.” Squamous Cell Carcinoma, Mar. 2012, doi:10.5772/25652
5. Pluquet, O., & Galmiche, A. (2019). Impact and Relevance of the Unfolded Protein Response in HNSCC. International Journal of Molecular Sciences, 20(11), 2654