Tumor suppressor BLU promotes TRAIL-induced apoptosis by downregulating NF-κB signaling in nasopharyngeal carcinoma

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.

Zinc finger myeloid Nervy DEAF-1 type (ZMYND) domain containing proteins exert molecular interactions to implicate in carcinogenesis

“…USP19/ZMYND9 is a deubiquitinase, capable of stabilizing the KPC1 (Kip1 ubiquitylation-promoting complex 1) ligase for p27Kip1, c-IAP1, and inhibiting the degradation of an anti-apoptotic molecule cellular inhibitor of apoptosis (cIAP) [145]; while it has been reported that BLU/ZMYND10 which engages intracellular NF-κB pathway to downregulate its transcriptionally activated factor like cIAP2 [17]. USP19/ZMYND9 also interacts with HIF-1α and several components of the hypoxia pathway to inhibit their degradation in a deubiquitinase independent manner [146][147][148].…”

Role of Adenoviruses in Cancer Therapy

“…One of the strategies that have been developed to use Ads in cancer therapy is to use replication-deficient adenoviral vectors to carry transgenes that codes for a tumor suppressor protein (p53) or proteins that induce apoptosis or cell cycle arrest ( 74 , 76 ). Wild-type p53 prevents development of cancer by inhibiting the activation of oncogenes and inducing programmed cell death (apoptosis) when the cell’s DNA repair functions are insufficient to repair DNA damage ( 77 ).…”

Adenoviral Vector-Based Vaccines and Gene Therapies: Current Status and Future Prospects

“…In some studies, replication-deficient or replication-competent adenoviral vectors were used to deliver transgenes, which express a tumor suppressor protein or cytotoxic/suicide protein that induces cell cycle arrest or a death cascade [176,177]. More than 50% of cancers have a mutation in tumor suppressor gene p53.…”