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Cancer Res. 2010 Jun 1;70(11):4655-65. doi: 10.1158/0008-5472.CAN-09-3953. Epub 2010 May 11.

Aurora-a is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells.

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  • 1Cellular and Molecular Oncology, Istituto Di Ricovero e Cura a Carattere Scientifico Fondazione Salvatore Maugeri, Pavia, Italy.

Abstract

Colorectal cancer stem cells (CR-CSC) are responsible for the generation and maintenance of intestinal tumors and are highly resistant to conventional chemotherapeutic agents. Aurora-A, a serine-threonine kinase involved in mitosis regulation, plays multiple key functions in tumor initiation and progression. We found that Aurora-A is overexpressed in primary colorectal tumor cells, in the CR-CSC fraction, and in stem cell-derived differentiated cells, compared with normal colon tissue. Aurora-A expression was functionally linked to centrosome amplification in CR-CSC, as indicated by the decrease in cells with multiple centrosomes that followed Aurora-A silencing. Knockdown of Aurora-A resulted in growth inhibition of CR-CSC, alteration of cell cycle kinetics, and downregulation of the expression levels of antiapoptotic Bcl-2 family members, strongly sensitizing to chemotherapy-induced cell death. Moreover, Aurora-A silencing compromised the ability to form tumor xenografts in immunocompromised mice and reduced the migratory capacity of CR-CSC. Altogether, these results indicate that Aurora-A is essential for CR-CSC regeneration and resistance to cytotoxic stimuli and suggest that therapies directed against Aurora-A may effectively target the stem cell population in colorectal cancer.

Copyright 2010 AACR.

PMID:
20460511
[PubMed - indexed for MEDLINE]
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