Assessing the efficacy and probable molecular mechanism of oncolytic measles virus-induced cell death in cultured nasopharyngeal carcinoma cells

Looi, Hong Keat (2024) Assessing the efficacy and probable molecular mechanism of oncolytic measles virus-induced cell death in cultured nasopharyngeal carcinoma cells. PhD thesis, UTAR.

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Abstract

Nasopharyngeal carcinoma (NPC) is often diagnosed at advanced stages and radiotherapy, the existing first-line treatment for NPC, often results in diverse functional defects around the head and neck region. Oncolytic measles virus (oMV) has shown potential as a new and gentle cancer therapeutics. However, their efficacy against NPC has yet to be explored. The present study aimed to assess the in-vitro efficacy of oMV in killing NPC with and without resistance to chemo- or radiotherapy and to elucidate the molecular mechanism involved in the oMV-induced cell killing. The infectivity and killing of NPC cells following infection with oMV were monitored by microscopy and quantitated by flow cytometry and cell viability assay. Differentially expressed peptides were quantitated using the iTRAQ-based assay. All NPC cell lines tested expressed CD46 and were efficiently infected by oMV. Infected NPC cells form syncytium at 24-hours post-infection, and cell loss was prominent at 48-hours post-infection. Proteomic analysis revealed that infected cells did not undergo apoptotic nor necrotic cell death pathway. However, HMGB1 and Rab GTPase 11a were found to be increased. HMGB1 functions as a damage-associated molecular pattern molecule that reportedly led to tumour cell killing via immune cell-mediated immunogenic cell death. Interestingly, both HMGB1 and Rab11a, a key molecule in endocytic trafficking, were reportedly involved in autophagy-associated active release of HMGB1 via exosome. Taken together, it is postulated that in this study, active release of HMGB1 could be mediated by autophagy induced by oMV infection, oMV-C, and -N proteins, leading to the formation of HMGB1-autophagy protein complexes followed by trafficking by Rab GTPases to host cell membrane, and consequently lead to extracellular release by exosome. Rab11a upregulation suggests that oMV-induced HMGB1 active release may involve Rab11a�dependant secretory pathway and HMGB1 plays can play a mediatory role in promoting autophagosome formation and enhances oMV-induced autophagic flux. Keywords: oncolytic measles virus; nasopharyngeal carcinoma; oncolytic virotherapy; immunogenic cell death; measles-induced oncolysis Subject Area: RZ409.7-999 Miscellaneous systems and treatments

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