SILAC Quantitative Proteomics and Biochemical Analyses Reveal a Novel Molecular Mechanism by Which ADAM12S Promotes the Proliferation, Migration, and Invasion of Small Cell Lung Cancer Cells through Upregulating Hexokinase 1

Small cell lung cancer (SCLC) accounts for ∼14% of total lung cancer, which is the worldwide leading cause of morbidity and mortality in cancer. Although SCLC can be treated with chemotherapy and radiotherapy, its 5 year survival rate is still below 7%. Therefore, it is essential to discover new molecules and elucidate the underlying mechanisms modulating the tumorigenesis and metastasis of SCLC for the unmet medical needs. The secreted form of A Disintegrin And Metalloproteinase 12 (ADAM12S) is highly expressed in SCLC and promotes the proliferation, migration, and invasion of SCLC cells. However, the underlying molecular mechanism is still elusive. Using stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomics, we identify 82 ADAM12S-regulated proteins in an SCLC cell line. Our proteomics and biochemical analyses discover that ADAM12S overexpression elevates while ADAM12 knockdown reduces the rate-limiting enzyme hexokinase 1 (HK1) in glycolysis. Through bioinformatics analyses, genetic manipulation, and in vitro assays, we further reveal that ADAM12S promotes the proliferation, colony formation, migration, and invasion of SCLC cells through upregulating HK1. This work links ADAM12S to glucose metabolic pathways in its attribution to the tumorigenesis and metastasis of SCLC cells and might provide valuable information for the exploration of therapeutic intervention for SCLC.