Targeting CD36 determines nicotine derivative NNK-induced lung adenocarcinoma carcinogenesis

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 alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR), sarcolemmal CD36 was increased and it interacted with surface alpha 7nAChR 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.

Automated summary

Carcinogenic nicotine-derived nitrosamine ketone (NNK) is the most potent factor in the development of lung adenocarcinoma (LUAD). This study revealed that the overexpression of fatty acid translocase CD36 is correlated with Src kinase activation, smoking status, metastasis, and worse overall survival in LUAD patients. The interaction between NNK, alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR), and CD36 plays a crucial role in activating Src and promoting LUAD tumor formation, which can be inhibited by CD36 knockdown or CD36 irreversible inhibitor SSO.