Activation of p53 pathway by Nutlin-3a inhibits the expression of the therapeutic target alpha 5 integrin in colon cancer cells

作者：Janouskova Hana; Ray Anne Marie; Noulet Fanny; Lelong Rebel Isabelle; Choulier Laurence; Schaffner Florence; Lehmann Maxime; Martin Sophie; Teisinger Jan; Dontenwill Monique^*

来源：Cancer Letters, 2013, 336(2): 307-318.

DOI：10.1016/j.canlet.2013.03.018

• Colon cancer
• Integrin alpha 5 beta 1
• p53
• Nutlin-3a
• RITA

Integrins emerge nowadays as crucial actors of tumor aggressiveness and resistance to therapies. Integrin 06131, the fibronectin receptor, determines malignant properties of colon carcinoma which is one of the most important causes of cancer-related deaths in the world. Here we show that inhibition of alpha 5 integrin subunit expression by siRNA or alpha 5 beta 1 integrin function by specific antagonist affects the survival of HCT116 colon cancer cells. We also evidence that pharmacological reactivation of the tumor suppressor p53 by Nutlin-3a inhibits specifically the expression of the alpha 5 integrin subunit both at the transcriptional and protein level. Inversely repression of alpha 5 integrin modulates p53 activity. A clear relationship between p53 activation by Nutlin-3a, alpha 5 repression and cell survival is shown. No such effects are obtained in cells lacking p53 or when another non-genotoxic activator of p53, RITA, is used. Our results emphasize the crucial role of alpha 5 beta 1 integrin in colon tumors. Data also suggest that interfering with the integrin (15131 through the reactivation of p53 by Nutlin-3a may be of valuable interest as a new therapeutic option for colon tumors expressing high level of the integrin and a wild type p53.

• 出版日期2013-8-19