Abstract
NSP 5a3a is a novel structural protein found to be over-expressed in certain cancer cell lines in-vitro such as Hela, Saos-2, and MCF-7 while barely detectable levels in normal body tissues except for Testis. This particular isoform has been known to interact with cyto- nuclear proteins B23, known to be involved in multi-faceted cellular processes such as cell division, apoptosis, ribosome biogenesis, and rRNA processing, as well as with hnRNP-L, known to be involved with RNA metabolism and rRNA processing. A previous preliminary investigation of NSP 5a3a as a potential target in Head and Neck Carcinoma revealed a novel p73 dependent mechanism through which NSP 5a3a induced apoptosis in Head and Neck cell lines when over-expressed in-vitro. Our present investigation further elucidated a novel dual axis signaling point by which NSP 5a3a induces apoptosis in Head and Neck cell line HN30 through p73-DAXX and TRAF2-TRADD. Interestingly, this novel mechanism appears independent of canonical caspases involved in the intrinsic mitochondrial pathway as well as those in the death receptor pathway thru TRAF2 and TRADD.
Highlights
Head and Neck squamous cell carcinomas (HNSSCs) being the fifth or sixth most common form of cancer worldwide depending on sources [8,9] has shown an increasing incidence with greater than 40,000 cases diagnosed each year in the United States and approximately 500,000 globally [10] though in the last forty years there has been no significant improvement in overall mortality and survival from this aggressive form of cancer [11,12]
Asynchronous HN30 cells were transfected with pcDNA3.0 NSP 5a3a vector along with controls after which images of the cells were taken three days post-transfection and prepared for immune-staining to assess the effect of NSP 5a3a over-expression on protein distribution of NSP 5a3a, p73, TRAF2, and TRADD
Immunostaining for TRAF2 in non-treated cells localized TRAF2 to both a diffuse localization in the cytoplasm and nucleus while in cells over-expressing NSP 5a3a, there seemed to be an increase of localization of TRAF2 into the cytoplasm as well as in association with protein bodies or aggregates as well as staining near and in likely association with apoptotic bodies (Fig. 5)
Summary
Head and Neck squamous cell carcinomas (HNSSCs) being the fifth or sixth most common form of cancer worldwide depending on sources [8,9] has shown an increasing incidence with greater than 40,000 cases diagnosed each year in the United States and approximately 500,000 globally [10] though in the last forty years there has been no significant improvement in overall mortality and survival from this aggressive form of cancer [11,12]. Given the general poor prognosis and high risk of cancerous recurrences even from secondary primary tumor sites, there is push through development of novel biologic therapies including gene therapy to promote better tumor growth control or regression with higher survival rates. Such strategies have included p53 based adenoviral gene therapy [21] as well as Fas ligand adenoviral gene therapy [22]
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