Thymosin beta 4 (T beta 4) is an actin-binding peptide overexpressed in several tumors, including colon carcinomas. The aim of this study was to investigate the role of T beta 4 in promoting the tumorigenic properties of colorectal cancer stem cells (CR-CSCs), which are responsible for tumor initiation and growth. We first found that CR-CSCs from different patients have higher T beta 4 levels than normal epithelial cells. Then, we used a lentiviral strategy to down-regulate T beta 4 expression in CR-CSCs and analyzed the effects of such modulation on proliferation, survival, and tumorigenic activity of CR-CSCs. Empty vector-transduced CR-CSCs were used as a control. Targeting of the T beta 4 produced CR-CSCs with a lower capacity to grow and migrate in culture and, interestingly, reduced tumor size and aggressiveness of CR-CSC-based xenografts in mice. Moreover, such loss in tumorigenic activity was accompanied by a significant increase of phosphatase and tensin homologue (PTEN) and a concomitant reduction of the integrin-linked kinase (ILK) expression, which resulted in a decreased activation of protein kinase B (Akt). Accordingly, exogenous expression of an active form of Akt rescued all the protumoral features lost after T beta 4 targeting in CR-CSCs. In conclusion, T beta 4 may have important implications for therapeutic intervention for treatment of human colon carcinoma.-Ricci-Vitiani, L., Mollinari, C., di Martino, S., Biffoni, M., Pilozzi, E., Pagliuca, A., Chiara de Stefano, M., Circo, R., Merlo, D., De Maria, R., Garaci, E. Thymosin beta 4 targeting impairs tumorigenic activity of colon cancer stem cells. FASEB J. 24, 4291-4301 (2010). www.fasebj.org
Thymosin beta 4 targeting impairs tumorigenic activity of colon cancer stem cells / L., Ricci Vitiani; C., Mollinari; DI MARTINO, Simona; M., Biffoni; Pilozzi, Emanuela; A., Pagliuca; M. C., De Stefano; R., Circo; D., Merlo; R., De Maria; E., Garaci. - In: THE FASEB JOURNAL. - ISSN 0892-6638. - 24:(2010), pp. 4291-4301. [10.1096/fj.10-159970]
Thymosin beta 4 targeting impairs tumorigenic activity of colon cancer stem cells
DI MARTINO, SIMONA;PILOZZI, Emanuela;
2010
Abstract
Thymosin beta 4 (T beta 4) is an actin-binding peptide overexpressed in several tumors, including colon carcinomas. The aim of this study was to investigate the role of T beta 4 in promoting the tumorigenic properties of colorectal cancer stem cells (CR-CSCs), which are responsible for tumor initiation and growth. We first found that CR-CSCs from different patients have higher T beta 4 levels than normal epithelial cells. Then, we used a lentiviral strategy to down-regulate T beta 4 expression in CR-CSCs and analyzed the effects of such modulation on proliferation, survival, and tumorigenic activity of CR-CSCs. Empty vector-transduced CR-CSCs were used as a control. Targeting of the T beta 4 produced CR-CSCs with a lower capacity to grow and migrate in culture and, interestingly, reduced tumor size and aggressiveness of CR-CSC-based xenografts in mice. Moreover, such loss in tumorigenic activity was accompanied by a significant increase of phosphatase and tensin homologue (PTEN) and a concomitant reduction of the integrin-linked kinase (ILK) expression, which resulted in a decreased activation of protein kinase B (Akt). Accordingly, exogenous expression of an active form of Akt rescued all the protumoral features lost after T beta 4 targeting in CR-CSCs. In conclusion, T beta 4 may have important implications for therapeutic intervention for treatment of human colon carcinoma.-Ricci-Vitiani, L., Mollinari, C., di Martino, S., Biffoni, M., Pilozzi, E., Pagliuca, A., Chiara de Stefano, M., Circo, R., Merlo, D., De Maria, R., Garaci, E. Thymosin beta 4 targeting impairs tumorigenic activity of colon cancer stem cells. FASEB J. 24, 4291-4301 (2010). www.fasebj.orgI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
