Thymosin beta4 targeting impairs tumorigenic activity of colon cancer stem cells.
Thymosin β4 (Tβ4) is an actin-binding peptide overexpressed in several tumors, including colon carcinomas. The aim of this study was to investigate the role of Tβ4 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 Tβ4 levels than normal epithelial cells. Then, we used a lentiviral strategy to down-regulate Tβ4 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 Tβ4 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 Tβ4 targeting in CR-CSCs. In conclusion, Tβ4 may have important implications for therapeutic intervention for treatment of human colon carcinoma.
Ricci-Vitiani
Lucia
L
Department of Hematology, Oncology, and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Mollinari
Cristiana
C
di Martino
Simona
S
Biffoni
Mauro
M
Pilozzi
Emanuela
E
Pagliuca
Alfredo
A
de Stefano
Maria Chiara
MC
Circo
Rita
R
Merlo
Daniela
D
De Maria
Ruggero
R
Garaci
Enrico
E
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000503:physiopathology*; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016086:Lentivirus / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000821:virology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013947:Thymosin / Q000378:metabolism*; D000099201:Thymosin beta(4); D000099200:Scaffold Protein ILK
D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D017346:Protein Serine-Threonine Kinases; D013947:Thymosin; D000099201:Thymosin beta(4); D000099200:Scaffold Protein ILK