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

Kim,Eun‑Ok; Kang,Shi‑Eun; Choi,Minji; Rhee,Ki‑Jong; Yun,Miyong

doi:10.3892/ijmm.2019.4425

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

Authors:
- Eun‑Ok Kim
- Shi‑Eun Kang
- Minji Choi
- Ki‑Jong Rhee
- Miyong Yun
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Affiliations: Department of Bioindustry and Bioresource Engineering, College of Life Sciences, Sejong University, Seoul 05006, Republic of Korea, Korean Medicine Clinical Trail Center, Kyung Hee University Korean Medicine Hospital, Seoul 02453, Republic of Korea, Medical Science Research Institute, Kyung Hee University Medical Center, Seoul 02453, Republic of Korea, Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University at Wonju, Wonju, Gangwon‑do 26493, Republic of Korea
Published online on: December 12, 2019 https://doi.org/10.3892/ijmm.2019.4425
Pages: 324-332
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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