SBI0206965, a novel inhibitor of Ulk1, suppresses non-small cell lung cancer cell growth by modulating both autophagy and apoptosis pathways

Tang,Fang; Hu,Pengchao; Yang,Zetian; Xue,Chao; Gong,Jun; Sun,Shaoxing; Shi,Liu; Zhang,Shimin; Li,Zhenzhen; Yang,Chunxu; Zhang,Junhong; Xie,Conghua

doi:10.3892/or.2017.5635

SBI0206965, a novel inhibitor of Ulk1, suppresses non-small cell lung cancer cell growth by modulating both autophagy and apoptosis pathways

Authors:
- Fang Tang
- Pengchao Hu
- Zetian Yang
- Chao Xue
- Jun Gong
- Shaoxing Sun
- Liu Shi
- Shimin Zhang
- Zhenzhen Li
- Chunxu Yang
- Junhong Zhang
- Conghua Xie
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Affiliations: Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China, Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China, Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
Published online on: May 10, 2017 https://doi.org/10.3892/or.2017.5635
Pages: 3449-3458

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Abstract

Lung cancer is a major public health problem worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases. Autophagy has recently sparked great interest, and it is thought to participate in a variety of diseases, including lung cancer. Uncoordinated (Unc) 51-like kinase 1 (Ulk1), a serine/threonine kinase, plays a central role in the autophagy pathway. However, the role of Ulk1 in NSCLC remains unclear. We report that NSCLC cell lines exhibited high expression of Ulk1 and that Ulk1 was negatively correlated with prognosis in lung cancer patients. Knockdown of Ulk1 or the inhibition of Ulk1 by the selective inhibitor SBI0206965, inhibited cell proliferation, induced cell apoptosis and enhanced the sensitivity of cisplatin against NSCLC cells. Moreover, we demonstrated that Ulk1 exerted oncogenic activity in NSCLC by modulating both autophagy and apoptosis pathways. Inhibition of autophagy by SBI0206965 sensitized NSCLC cells to cisplatin by inhibiting cisplatin induced cell-protective autophagy to promote apoptosis. Furthermore, SBI0206965 promoted apoptosis in NSCLC cells independent of autophagy, which was partly mediated by destabilization of Bcl2/Bclxl. In summary, our results show that inhibition of Ulk1 suppresses NSCLC cell growth and sensitizes NSCLC cells to cisplatin by modulating both autophagy and apoptosis pathways, and that Ulk1 might be a promising target for NSCLC treatment.

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