Stathmin Serine 16 Phosphorylation Is a Key Regulator of Cell Cycle Progression Without Activating Metastatic Behavior

Background: Treatment of metastatic cancer remains a challenge, because cancer cells acquire resistance even to the most contemporary therapies. This study analyzed the role of the phosphoprotein Stathmin 1 (STMN1) in regulating cancer cell growth and metastatic potential.Methods: Public datasets with metastatic castration-resistant prostate cancer (mCRPC) and breast cancer (BC) were analyzed to determine the interrelationship between STMN1, hepatocyte growth factor (HGF), and MET proto-oncogene (MET) expression, overall survival, and response to chemotherapy. Site-directed mutagenesis, cell cycle analysis, proliferation, migration and invasion assays determined the impact of STMN1 phosphorylation on proliferation and metastatic potential. Results: Increased STMN1 associates with HGF and MET gene expression in mCRPC, and taxane chemotherapy further increases HGF expression. STMN1 and HGF are highest, and overall survival is poorest in mCRPC to liver compared to other sites, implying the metastatic site influences their expression levels and potentially pattern of metastatic spread. Increased STMN1 and MET also predict taxane responsiveness in BC patients. Analysis of STMN1 serine (S)16, 25, 38, and 63 determined total (t) STMN1 and STMN1 S16 phosphorylation (pSTMN1S16) are co-regulated by HGF/MET during cell cycle progression, pSTMN1S16 alone can promote cell proliferation, and pSTMN1S16 shortens the cell cycle similar to HGF treatment, while STMN1S16 dephosphorylation lengthens the cell cycle to arrest cell growth in G2/M, similar to HGF plus the MET inhibitor AMG337. Importantly, STMN1S16 does not promote metastasis. Conclusion: Selectively inhibiting STMN1S16 phosphorylation may provide an alternative strategy for inhibiting MET-mediated cell growth to eliminate metastatic cancer cells and inhibit further metastasis.