Unbiased proteomic and transcript analyses reveal that stathmin-1 silencing inhibits colorectal cancer metastasis and sensitizes to 5-fluorouracil treatment.

Abstract

UNLABELLED:

Colorectal cancer metastasis is a major cause of mortality worldwide, which may only be controlled with novel methods limiting tumor dissemination and chemoresistance. High stathmin-1 (STMN1) expression was previously established as a hallmark of colorectal cancer progression and predictor of poor survival; however, the mechanism of action is less clear. This work demonstrates that STMN1 silencing arrests tumor-disseminative cascades by inhibiting multiple metastatic drivers, and repressing oncogenic and mesenchymal transcription. Using a sensitive iTRAQ labeling proteomic approach that quantified differential abundance of 4562 proteins, targeting STMN1 expression was shown to reinstate the default cellular program of metastatic inhibition, and promote cellular adhesion via amplification of hemidesmosomal junctions and intermediate filament tethering. Silencing STMN1 also significantly improved chemoresponse to the classical colorectal cancer therapeutic agent, 5FU, via a novel caspase-6 (CASP6)-dependent mechanism. Interestingly, the prometastatic function of STMN1 was independent of p53 but required phosphorylations at S25 or S38; abrogating phosphorylative events may constitute an alternative route to achieving metastatic inhibition. These findings establish STMN1 as a potential target in antimetastatic therapy, and demonstrate the power of an approach coupling proteomics and transcript analyses in the global assessment of treatment benefits and potential side-effects.

IMPLICATIONS:

Stathmin-1 is a potential candidate in colorectal cancer therapy that targets simultaneously the twin problems of metastatic spread and chemoresistance.

• Authors: Wei Wu, Xing Fei Tan, Hwee Tong Tan, Teck Kwang Lim, Maxey Ching Ming Chung
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 12 Issue 12 Pg. 1717-28 (Dec 2014) ISSN: 1557-3125 [Electronic] United States
• PMID: 25063586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antimetabolites, Antineoplastic
• STMN1 protein, human
• Stathmin
• Fluorouracil

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Epithelial-Mesenchymal Transition (drug effects)
• Fluorouracil (pharmacology)
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• HCT116 Cells
• Humans
• Neoplasm Metastasis
• Proteomics (methods)
• Signal Transduction (drug effects)
• Stathmin (genetics, metabolism)