TY - JOUR
T1 - Aurora-A is essential for the tumorigenic capacity and chemoresistance of colorectal cancer stem cells
AU - Cammareri, Patrizia
AU - Scopelliti, Alessandro
AU - Todaro, Matilde
AU - Eterno, Vincenzo
AU - Francescangeli, Federica
AU - Moyer, Mary Pat
AU - Agrusa, Antonino
AU - Dieli, Francesco
AU - Zeuner, Ann
AU - Stassi, Giorgio
PY - 2010/6/1
Y1 - 2010/6/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-09-3953
DO - 10.1158/0008-5472.CAN-09-3953
M3 - Article
C2 - 20460511
AN - SCOPUS:77953164298
VL - 70
SP - 4655
EP - 4665
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 11
ER -