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EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism

1
Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia
2
Cell Structure and Mechanobiology Group, Department of Biomedical Engineering, Melbourne School of Engineering, The University of Melbourne, Parkville, VIC 3010, Australia
3
Department of Physiology, The University of Melbourne, Parkville, VIC 3010, Australia
4
Olivia Newton-John Cancer Research Institute, La Trobe University, Heidelberg, VIC 3084, Australia
5
Department of Neurosurgery, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia
6
Department of Neurosurgery, Hadassah Hebrew University Medical Centre, Jerusalem 91120, Israel
*
Author to whom correspondence should be addressed.
Academic Editor: Naoto T. Ueno
Cancers 2021, 13(6), 1198; https://doi.org/10.3390/cancers13061198
Received: 21 February 2021 / Revised: 2 March 2021 / Accepted: 4 March 2021 / Published: 10 March 2021
(This article belongs to the Section Molecular Cancer Biology)
A key molecule, EGFRvIII has been shown to provide several growth advantages for brain tumors. However, we have found a new mechanism in which the EGFRvIII provides increased survival to brain cancer cells when under sub-optimal conditions. Specifically, we have found that the EGFRvIII drives the expression of a molecule called Reticulocalbin 1 (RCN1) and that RCN1 blocks cell stress and cell death, thereby allowing cells to survive and proliferate. Importantly, these findings will allow for the generation of drugs that block the function of EGFRvIII and RCN1 with the hope that these drugs will induce brain cancer cell death.
Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress. View Full-Text
Keywords: EGFRvIII; RCN1; ER stress; apoptosis; glioblastoma EGFRvIII; RCN1; ER stress; apoptosis; glioblastoma
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MDPI and ACS Style

Gomez, J.; Areeb, Z.; Stuart, S.F.; Nguyen, H.P.T.; Paradiso, L.; Zulkifli, A.; Madan, S.; Rajagopal, V.; Montgomery, M.K.; Gan, H.K.; Scott, A.M.; Jones, J.; Kaye, A.H.; Morokoff, A.P.; Luwor, R.B. EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism. Cancers 2021, 13, 1198. https://doi.org/10.3390/cancers13061198

AMA Style

Gomez J, Areeb Z, Stuart SF, Nguyen HPT, Paradiso L, Zulkifli A, Madan S, Rajagopal V, Montgomery MK, Gan HK, Scott AM, Jones J, Kaye AH, Morokoff AP, Luwor RB. EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism. Cancers. 2021; 13(6):1198. https://doi.org/10.3390/cancers13061198

Chicago/Turabian Style

Gomez, Juliana, Zammam Areeb, Sarah F. Stuart, Hong P.T. Nguyen, Lucia Paradiso, Ahmad Zulkifli, Sonakshi Madan, Vijay Rajagopal, Magdalene K. Montgomery, Hui K. Gan, Andrew M. Scott, Jordan Jones, Andrew H. Kaye, Andrew P. Morokoff, and Rodney B. Luwor 2021. "EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism" Cancers 13, no. 6: 1198. https://doi.org/10.3390/cancers13061198

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