Aurora-A Is Essential for the Tumorigenic Capacity and Chemoresistance of Colorectal Cancer Stem Cells

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 pro...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2010-06, Vol.70 (11), p.4655-4665
Main Authors: CAMMARERI, Patrizia, SCOPELLITI, Alessandro, TODARO, Matilde, ETERNO, Vincenzo, FRANCESCANGELI, Federica, PAT MOYER, Mary, AGRUSA, Antonino, DIELI, Francesco, ZEUNER, Ann, STASSI, Giorgio
Format: Article
Language:English
Subjects:
Aged
Animals
Antineoplastic agents
Aurora Kinase A
Aurora Kinases
Biological and medical sciences
Cell Cycle - genetics
Cell Growth Processes - genetics
Cell Movement - genetics
Centrosome - physiology
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - enzymology
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Drug Resistance, Neoplasm
Female
Gastroenterology. Liver. Pancreas. Abdomen
Gene Amplification
Gene Knockdown Techniques
Humans
Male
Medical sciences
Mice
Mice, Nude
Middle Aged
Neoplastic Stem Cells - enzymology
Neoplastic Stem Cells - pathology
Pharmacology. Drug treatments
Protein-Serine-Threonine Kinases - biosynthesis
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
Tumors
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-09-3953