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.