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.

Cammareri, P., Scopelliti, A., Todaro, M., Eterno, V., Francescangeli, F., Moyer, M.P., et al. (2010). Aurora-a is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells. CANCER RESEARCH, 11, 4655-4665 [10.1158/0008-5472.CAN-09-3953].

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

CAMMARERI, Patrizia;SCOPELLITI, Alessandro;TODARO, Matilde;ETERNO, Vincenzo;AGRUSA, Antonino;DIELI, Francesco;STASSI, Giorgio
2010

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.
Cammareri, P., Scopelliti, A., Todaro, M., Eterno, V., Francescangeli, F., Moyer, M.P., et al. (2010). Aurora-a is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells. CANCER RESEARCH, 11, 4655-4665 [10.1158/0008-5472.CAN-09-3953].
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10447/51283
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