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Caspase‐9b Directly Interacts with c‐IAP1 to Drive an Agonist‐Independent Activation of the NF‐κB Pathway and the Enhancement of Tumorigenicity in Non‐Small Cell Lung Cancer
Author(s) -
Vu Ngoc,
Park Margaret,
Shultz Michael,
Ladd Amy,
Chalfant Charles
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.894.2
Subject(s) - nf κb , caspase 8 , gene isoform , apoptosis , cancer research , microbiology and biotechnology , inhibitor of apoptosis , signal transduction , biology , nfkb1 , iκb kinase , transcription factor , chemistry , caspase , programmed cell death , gene , biochemistry
Caspase‐9 has two isoforms with opposing functions, pro‐apoptotic caspase‐9a (C9a) and anti‐apoptotic caspase‐9b (C9b). C9b expression has been reported to augment the anchorage‐dependent growth and tumorigenic capacity of non‐small cell lung cancer (NSCLC) cells; however, the mechanism of this biological observation was unknown. Herein for the first time, C9b is shown to have a dual function in regulating the survival/oncogenic nuclear factor κB (NF‐κB) pathway, which is independent from modulating C9a activation. In particular, C9b is shown to activate the canonical arm and inhibit of the non‐canonical arm of the NF‐κB pathway by destabilizing NF‐κB inhibitor alpha (IκB‐α) and NF‐κB‐inducing kinase (NIK). Importantly, this new role for C9b contributes to the enhanced survival and anchorage‐independent growth of NSCLC cells conferred by C9b expression. Further mechanistic studies demonstrated a direct association of C9b with the cellular inhibitor of apoptosis 1 (c‐IAP1), a regulatory factor in both arms of the NF‐κB network, via its IAP‐binding motif (IBM). Through this interaction, C9b induces the E3 ligase activity of c‐IAP1, which regulates NF‐κB activation, and promotes the viability, anchorage‐independent growth and tumorigenicity of NSCLC cells. Lastly, the link between C9b expression and NF‐κB activation was validated in human NSCLC tumors. Overall, a novel tumorigenic mechanism has been identified by which alternative mRNA processing leads to generation of a protein isoform that regulates the NF‐κB signaling independent of external agonist.