Targeting CD36 determines nicotine derivative NNK-induced lung adenocarcinoma carcinogenesis

Ming-Yue Li; Menghuan Wang; Ming Dong; Zangshu Wu; Rui Zhang; Bowen Wang; Yuxi Huang; Xiaoyang Zhang; Jiaying Zhou; Junbo Yi; George Gong Chen; Li-Zhong Liu

doi:10.1016/j.isci.2023.107477

Targeting CD36 determines nicotine derivative NNK-induced lung adenocarcinoma carcinogenesis

iScience. 2023 Jul 27;26(8):107477. doi: 10.1016/j.isci.2023.107477. eCollection 2023 Aug 18.

Authors

Ming-Yue Li^{1

2}, Menghuan Wang¹, Ming Dong^{1

2}, Zangshu Wu^{1

2}, Rui Zhang^{1

2}, Bowen Wang¹, Yuxi Huang¹, Xiaoyang Zhang¹, Jiaying Zhou¹, Junbo Yi¹, George Gong Chen³, Li-Zhong Liu¹

Affiliations

¹ Department of Physiology, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, Guangdong, China.
² GuangZhou National Laboratory, No.9 XingDaoHuanBei Road, Guangzhou International Bio Island, Guangzhou 510005, Guangdong Province, China.
³ Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.

Abstract

Smoking carcinogen nicotine-derived nitrosamine ketone (NNK) is the most potent contributor to lung adenocarcinoma (LUAD) development, but the mechanism has not been fully elucidated. Here, we reported that fatty acid translocase CD36 was significantly overexpressed in both human LUAD tissues and NNK-induced A/J mice LUAD tumors. The overexpressed CD36 was positively correlated with Src kinase activation, smoking status, metastasis, and worse overall survival of patients with smoking history. Upon NNK binding with α7 nicotinic acetylcholine receptor (α7nAChR), sarcolemmal CD36 was increased and it interacted with surface α7nAChR and cytosol Src simultaneously, which in turn activated Src and downstream pro-carcinogenic kinase ERK1/2 and Akt, and finally caused LUAD cells to form subcutaneous and pulmonary metastatic tumors. This process could be blocked by CD36 knockdown and CD36 irreversible inhibitor SSO. Furthermore, the effect of NNK was inhibited obviously in CD36^-/- A/J mice. Thus, targeting CD36 may provide a breakthrough therapy of LUAD.

Keywords: Cancer; Cell biology; Molecular biology.