CCR4‑NOT transcription complex subunit�2�regulates TRAIL sensitivity in non‑small‑cell lung cancer cells via the STAT3 pathway

Abstract

TRAIL is an attractive candidate for anticancer therapy in a variety of tumors since it targets only tumors and not normal tissue. However, a remaining major hurdle is that the majority of tumors exhibit a resistance mechanism against the effects of TRAIL via the induction of anti-apoptotic signaling pathways. In this study, we aimed to evaluate whether the modulation of ccR4-NOT transcription complex subunit 2 (cNOT2) function can promote TRAIL sensitivity in non-small-cell lung cancer (NScLc) cells. cNOT2 depletion partially decreased colony numbers and the proliferation of NScLc cells. When combined with TRAIL, the suppression of cNOT2 expression markedly decreased the survival rate and increased apoptosis, as compared with TRAIL treatment alone in TRAIL-resistant NScLc cells. Of note, cNOT2 overexpression in TRAIL-sensitive H460 cells enhanced the survival rate and decreased apoptosis when compared with TRAIL treatment alone. Gene expression analysis indicated that genes involved in the signal transducer and activator of transcription 3 (STAT3) signaling pathway were dominantly altered in the cNOT2-depleted A549 cells. Under this condition, Src homology region 2 domain containing phosphatase-1 (SHP1) was significantly upregulated and subsequently increased apoptosis. On the whole, the findings of this study demonstrate that cNOT2 participates in TRAIL sensitivity in NScLc cells via the regulation of the STAT3 signaling pathway, and suggest that combination therapy with cNOT2 depletion and TRAIL treatment may prove to be a useful strategy for overcoming TRAIL resistance in NScLc.

TRAIL mediated signaling in different cancers: cancer in the "Crosshairs"

“…Moreover, CNOT2, one of the CCR4-NOT subunits played a central role in enhancing TRAIL-resistance. CNOT2 knockdown markedly increased TRAIL sensitivity in H1299 and A549 cells (13).…”

“…CCR4-NOT transcription complex (CNOT), composed of 11 subunits has been shown to participate in multiple cellular processes (13). Moreover, CNOT2, one of the CCR4-NOT subunits played a central role in enhancing TRAIL-resistance.…”

Multiplatform discovery and regulatory function analysis of structural variations in non-small cell lung carcinoma

“…In addition, we also identified some DEGs that may be candidate oncogenes, for example, CNOT2 (Figure 5B, Wilcoxon rank-sum test, p = 0.0019, log2(fold change) = 1.148), which encodes a protein that participates in metastasis, angiogenesis, and other tumor progression processes (Ito et al, 2011;Sohn et al, 2018). The combination of CNOT2 depletion and TRAIL treatment was suggested to be a useful strategy for overcoming TRAIL resistance in NSCLC (Kim et al, 2020). cAMP-dependent protein kinase inhibitor alpha (PKIA) encodes an inhibitor of cyclic AMP-dependent protein kinase A (PKA) activity (cAMP), which interacts with and inhibits the activities of subunits of PKA.…”

Prevalence, causes and impact ofTP53-loss phenocopying events in human tumors

“…CNOT2 depletion and CCR4-NOT disruption have been linked to an apoptotic response via MID1IP1 and increased p53 activity (70, 72). CNOT2 has been reported to be among the top 5 amplified genes in chromosome 12, together with MDM2 (73). Appealingly its overexpression has been demonstrated in several cancer types such as pancreas, prostate, liver, urinary, ovarian and breast (71).…”

“…Appealingly its overexpression has been demonstrated in several cancer types such as pancreas, prostate, liver, urinary, ovarian and breast (71). Experiments inducing CNOT2 overexpression led to increased p21 and p53 expression, decreased apoptosis and decreased TNF-related apoptosis-inducing ligand (TRAIL) sensitivity (72, 73).…”