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 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
Patrizia
P
Cellular and Molecular Oncology, Istituto Di Ricovero e Cura a Carattere Scientifico Fondazione Salvatore Maugeri, Pavia, Italy.
Scopelliti
Alessandro
A
Todaro
Matilde
M
Eterno
Vincenzo
V
Francescangeli
Federica
F
Moyer
Mary Pat
MP
Agrusa
Antonino
A
Dieli
Francesco
F
Zeuner
Ann
A
Stassi
Giorgio
G
D000368:Aged; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002453:Cell Cycle / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D018385:Centrosome / Q000502:physiology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*
C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases