Stathmin Serine 16 Phosphorylation Is a Key Regulator of Cell Cycle Progression Without Activating Migration and Invasion In Vitro

TL;DR

This study shows that phosphorylation of Stathmin 1 at serine 16 promotes cancer cell growth but not metastasis, suggesting a new strategy to treat metastatic prostate and breast cancer.

Contribution

The study identifies Stathmin 1 serine 16 phosphorylation as a key regulator of cell growth without promoting metastasis in prostate and breast cancer.

Findings

High Stathmin 1 levels correlate with poor survival in metastatic prostate and breast cancer.

Phosphorylation of Stathmin 1 at serine 16 promotes cell proliferation but not migration or invasion.

Inhibiting Stathmin 1 serine 16 phosphorylation could help treat metastatic cancer without promoting further spread.

Abstract

Treating metastatic prostate cancer is challenging because it will become resistant to most forms of treatment. This study investigated Stathmin 1, a protein that regulates cancer cell growth, and found that Stathmin 1 levels were high in metastatic breast and prostate cancer. High Stathmin 1 expression was also associated with poor overall survival, and survival worsened when prostate cancer metastasized to the liver compared to other organs. In cell culture assays, the addition of a phosphate molecule to serine 16 on the Stathmin 1 protein increased cancer cell growth, while removing the phosphate inhibited cell growth. Notably, Stathmin 1 phosphorylated on serine 16 did not promote metastasis. Thus, selectively preventing Stathmin 1 serine 16 phosphorylation may provide an alternative strategy for inhibiting growth factor-mediated metastatic cell growth in combination with current therapies used to eliminate metastatic cancer cells while preventing/inhibiting further metastasis.

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, and 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 in the liver compared to other sites, implying the metastatic site influences their expression levels and potentially the 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 that 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. Conclusions: Selectively inhibiting STMN1S16 phosphorylation may provide an alternative strategy for inhibiting MET-mediated cell growth to eliminate metastatic cancer cells and inhibit further metastasis.

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