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Abstract
A putative tumor suppressor BLU mapped on the chromosomal 3p21 region, is frequently lost in human tumors including nasopharyngeal carcinoma (NPC). To explore the underlying mechanism of tumor suppression by BLU, its potential to promote apoptosis induced by TRAIL, an effector molecule elaborated by natural killer-T (NKT) cells was investigated. BLU was re-expressed in NPC-derived HNE1 cells by recombinant adenoviral infection and the cells were challenged with recombinant TRAIL. The growth inhibition of BLU was assayed and apoptosis was examined by flow cytometry-based tetramethylrhodamine ethyl ester (TMRE) and annexin V staining, cleavage of pro-caspase-8 and poly ADP ribose polymerase (PARP). The modulation of NF-κB pathway by BLU was evaluated by the reporter activity and estimation of the level of the molecules involved such as IKKalpha, p65 NF-κB, as well as NF-κB induced anti-apoptotic factors cFLIPL and cIAP2. The expression of BLU exerted in vitro and in vivo growth inhibitory effect and promoted TRAIL-induced apoptosis. This phenomenon was validated by FACS-based assays of mitochondrial membrane potential (BLU vs. Vector 87.8% ± 7.7% and 72.1%±6.7% at 6h exposure to TRAIL) and phosphatidylserine turnover (BLU vs. vector: 28.7%±2.9% and 22.6%±2.5%), as well as, enhanced caspapse-8 cleavage. Similar with the findings that BLU promotes chemotherapeutic agent-induced apoptosis, it also augmented death receptor-induced pathway through NF-κB pathway inhibition. In conclusion, BLU suppressed tumor formation by strengthening the antitumor immunity.
Highlights
Nasopharyngeal carcinoma (NPC) is a head and neck cancer arising from the epithelial cells in the lining of nasopharynx [1]
The epigenetic and/or genetic inactivation of Tumor suppressor genes (TSGs) contributes towards the occurrence of malignancy, because of the loss of functions such as inhibition of cell cycle entry and triggering of apoptosis in the host [21, 22]
It has been reported that the re-expression of the frequently lost TSGs restores the normal modulation of cell cycle entry and apoptosis by inhibition of some signaling pathway [32,33,34,35]
Summary
Nasopharyngeal carcinoma (NPC) is a head and neck cancer arising from the epithelial cells in the lining of nasopharynx [1]. The differences in the geographical and racial distribution indicate the multifactorial etiology of the particular tumor; these include environmental factors, food consumption, the infection of Epstein-Barr virus (EBV), a lymphotropic human herpesvirus, and genetic susceptibility. This remarkable distribution of NPC indicates that the development of nasopharyngeal cancer may be associated with the genetic and environmental factors [3]. Radiotherapy and concurrent chemoradiotherapy are the primary treatments of primary NPC [6]. The tumor cells of NPC are sensitive to radiotherapy; the use of radiotherapy, www.impactjournals.com/oncotarget chemoradiotherapy, or targeted radiotherapy has not significantly improved the survival rate of the patients. Elucidation of the underlying mechanism of NPC genesis is necessitated in order to improve the efficacy of the therapy
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