title: Melanoma differentiation associated gene-7/interleukin-24 induces caspase-3 denitrosylation to facilitate the activation of cancer cell apoptosis.
abstract: Melanoma differentiation-associated gene-7 (mda-7)/interleukin-24 (IL-24) induces caspase-3 cleavage and subsequent activation via the intrinsic or extrinsic pathway to result in cancer cell-selective apoptosis, but whether mda-7/IL-24 may directly regulate caspase-3 through the post-translational modification remains unknown. Here, we reported that tumor-selective replicating adenovirus ZD55-IL-24 led to caspase-3 denitrosylation and subsequent activation, indicating that caspase-3 denitrosylation played a crucial role in ZD55-IL-24-induced cancer cell apoptosis. To confirm the relationship between caspase-3 denitrosylation and its activation in response to ZD55-IL-24, we treated carcinoma cells with the different nitric oxide (NO) regulators to modulate caspase-3 denitrosylation level, then observed the corresponding caspase-3 cleavage. We found that NO inhibitor 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide (PTIO) promoted caspase-3 denitrosylation and caspase-3 cleavage, thereby exacerbating ZD55-IL-24-induced cancer cell apoptosis, whereas NO donor sodium nitroprusside (SNP) showed the opposite effect. Moreover, caspase-3 denitrosylation facilitated its downstream target poly ADP-ribose polymerase (PARP) degradation that further increased the apoptotic susceptibility. Although caspase-3 activation controlled by denitrosylation modification has emerged as an important regulator of programmed cell death, the detailed molecular mechanism by which caspase-3 exerts its denitrosylation modification in response to ZD55-IL-24 still needs to be elucidated. Thus, our results demonstrated that ZD55-IL-24 increased Fas expression to enhance thioredoxin reductase 2 (TrxR2), which was responsible for caspase-3 denitrosylation. Collectively, these findings elucidate that ZD55-IL-24 induces caspase-3 denitrosylation through Fas-mediated TrxR2 enhancement, thereby facilitating caspase-3 cleavage and the downstream caspase signaling pathway activation, which provides a novel insight into ZD55-IL-24-induced cancer-specific apoptosis by post-translational modification of the apoptotic executor caspase-3.
authors.affiliation: Laboratory of Biological Cancer Therapy, Xuzhou Medical College , Xuzhou, Jiangsu, P.R. China .
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.forename: De-Fang
authors.initials: DF
authors.lastname: Zhang
authors.forename: Bao-Fu
authors.initials: BF
authors.lastname: Zhang
authors.forename: Hui-Zhong
authors.initials: HZ
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Lian-Tao
authors.initials: LT
authors.lastname: Li
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Pei
authors.forename: Jun-Nian
authors.initials: JN
authors.lastname: Zheng
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D003001:Cloning, Molecular; D018014:Gene Transfer Techniques; D006367:HeLa Cells; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D011499:Protein Processing, Post-Translational / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D054482:Thioredoxin Reductase 2 / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D019014:fas Receptor / Q000378:metabolism; D000099180:Interleukin-24
chemical_list: D053148:Caspase 3; D007378:Interleukins; D054482:Thioredoxin Reductase 2; D019014:fas Receptor; D000099180:Interleukin-24; C516127:TXNRD2 protein, human