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DDIAS suppresses TRAIL-mediated apoptosis by inhibiting DISC formation and destabilizing caspase-8 in cancer cells

Abstract

DNA damage-induced apoptosis suppressor (DDIAS) has an anti-apoptotic function during DNA damage in lung cancer. However, the anti-apoptotic mechanism of DDIAS in cancer cells under other conditions has not been reported. We report here that DDIAS protects cancer cells from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by two distinct mechanisms in non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) cells. DDIAS depletion sensitized NSCLC and HCC cells to TRAIL-mediated apoptosis, an effect that was abrogated by pharmacological or genetic inhibition of caspase-8 and was independent of caspase-9, p53, or mitogen-activated protein kinase signaling. Interestingly, we found that the N terminus of DDIAS interacted with the death effector domain of Fas-associated protein death domain (FADD) and prevented its recruitment to the death-inducing signaling complex (DISC), thereby blocking caspase-8 activation. DDIAS knockdown also suppressed epidermal growth factor-induced phosphorylation of p90 ribosomal S6 kinase (RSK) 2 and stabilized caspase-8 by preventing its ubiquitination and proteasomal degradation. This effect was abolished by RSK2 overexpression. Taken together, DDIAS has dual functions in inhibiting DISC formation as well as in destabilizing caspase-8, thereby suppressing TRAIL-mediated apoptosis of cancer cells. Thus, we suggest that DDIAS can serve as an effective therapeutic target in the treatment of NSCLC and HCC.

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Fig. 1: DDIAS knockdown enhances TRAIL-induced apoptotic cell death.
Fig. 2: DDIAS overexpression protects cells from TRAIL-induced apoptosis.
Fig. 3: Neither p53 nor DR5 is involved in TRAIL-induced apoptosis resulting from DDIAS knockdown.
Fig. 4: Caspase-8 is required for DDIAS knockdown-induced TRAIL sensitivity.
Fig. 5: DDIAS interacts with FADD to block DISC formation.
Fig. 6: DDIAS regulates caspase-8 stability by activating RSK2.
Fig. 7: Model of DDIAS-mediated caspase-8 regulation.

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Acknowledgments

This work was supported by the KRIBB Initiative Program (KGM4751713), National Research Foundation (NRF; 2017R1A2B2011936 and 2017M3A9F9030565), and Health Technology R&D (HI13C2162).

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Correspondence to Misun Won.

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The authors declare that they have no competing interests.

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Joo-Young Im and Bo-Kyung Kim contributed equally to this work.

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Im, JY., Kim, BK., Lee, JY. et al. DDIAS suppresses TRAIL-mediated apoptosis by inhibiting DISC formation and destabilizing caspase-8 in cancer cells. Oncogene 37, 1251–1262 (2018). https://doi.org/10.1038/s41388-017-0025-y

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