Dapk2 Activates Nf-Kappa B Through Autophagy-Dependent Degradation Of I-Kappa B Alpha During Thyroid Cancer Development And Progression

Background: Death- associated protein kinase 2 (DAPK2) is a serine/threonine kinase, which has been implicated in autophagy and apoptosis. DAPK2 functions as a tumor suppressor in various cancers. However, the role of DAPK2 in thyroid cancer (TC) is unclear.Methods: RNA sequencing of human TC samples was performed to identify differentially expressed genes that may play a role in TC development. The messenger RNA (mRNA) expression of DAPK2 was verified by quantitative real-time polymerase chain reaction (qRT-PCR). To investigate the role of DAPK2 in TC development, DAPK2 was knocked down and overexpressed in a TTA1 cell line. The effect of DAPK2 on cell proliferation, sensitization of TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis and tumor growth was examined. The effect of DAPK2 on autophagy and NF-kappa B activation was investigated to address the underlying mechanism.Results: DAPK2 was upregulated in TC. Knockdown of DAPK2 in TTA1 cells led to reduced cell proliferation, sensitization of TRAIL-induced apoptosis, and restricted tumor growth both in vitro and in vivo, while overexpression of DAPK2 exhibited the opposite effect. Mechanistically, DAPK2 promoted autophagy as demonstrated by the accumulation of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, which correlated with the level of nuclear factor-kappa B (NF-kappa B) activation. Knockdown of inhibitory-kappa B alpha (I-kappa B alpha) in short hairpin (sh) DAPK2 TTA1 cells restored the activity of NF-kappa B, suggesting DAPK2 activated NF-kappa B through autophagy-mediated I-kappa B alpha degradation.Conclusions: Our findings revealed a pivotal role of DAPK2 in thyroid carcinogenesis, being required for tumor growth and for resistance to TRAIL-induced apoptosis through autophagy-mediated I-kappa B alpha degradation. This result provides a novel target for the therapy of TC.