Y Li1, D Chen, F-Y Hao, K-J Zhang. 1. Department of General Surgery, Department of Pathology; the Affiliated Hospital of Qingdao University, Qingdao, China. zkejun@yahoo.ca.
Abstract
OBJECTIVE: We have recently reported that therapies targeting TGF-β1 signaling were effective to prevent the anaplastic thyroid cancer (ATC) cell growth, but not the invasion. Phosphatidylinositol 3-kinase (PI3K)/AKT signaling are activated in ATC and play a major role in ATC invasion. Herein, we examined the effects of targeting TGF-β1 by shRNA in combination with pan-AKT inhibitor, MK-2206 on growth and metastasis of ATC xenografts implanted in severe combined immunodeficient mice. MATERIALS AND METHODS: 8505C cells or 8505C/shRNA cells or 8505C/TGF-β1 shRNA cells were implanted sc in 5-week-old female nude mice. Upon establishment of palpable tumours, MK-2206 was administered at 60 mg/kg, orally, three times a week for 6 weeks. RESULTS: The results showed that TGF-β1/shRNA alone only prevents anaplastic thyroid cancer (ATC) tumor formation, but not lung metastasis. MK-2206 alone only inhibits lung metastasis, but not tumor formation. The combined treatment with TGF-β1/shRNA and MK-2206 led to an approximately 71% growth inhibition compared with TGF-β1/shRNA (44%) and MK-2206 (15%). The combined treatment with TGF-β1/shRNA and MK-2206 significantly inhibits lung metastasis. CONCLUSIONS: These findings demonstrated that targeting TGF-β1 in combination with MK-2206 was the effective method for treatment of ATC.
OBJECTIVE: We have recently reported that therapies targeting TGF-β1 signaling were effective to prevent the anaplastic thyroid cancer (ATC) cell growth, but not the invasion. Phosphatidylinositol 3-kinase (PI3K)/AKT signaling are activated in ATC and play a major role in ATC invasion. Herein, we examined the effects of targeting TGF-β1 by shRNA in combination with pan-AKT inhibitor, MK-2206 on growth and metastasis of ATC xenografts implanted in severe combined immunodeficientmice. MATERIALS AND METHODS: 8505C cells or 8505C/shRNA cells or 8505C/TGF-β1 shRNA cells were implanted sc in 5-week-old female nude mice. Upon establishment of palpable tumours, MK-2206 was administered at 60 mg/kg, orally, three times a week for 6 weeks. RESULTS: The results showed that TGF-β1/shRNA alone only prevents anaplastic thyroid cancer (ATC) tumor formation, but not lung metastasis. MK-2206 alone only inhibits lung metastasis, but not tumor formation. The combined treatment with TGF-β1/shRNA and MK-2206 led to an approximately 71% growth inhibition compared with TGF-β1/shRNA (44%) and MK-2206 (15%). The combined treatment with TGF-β1/shRNA and MK-2206 significantly inhibits lung metastasis. CONCLUSIONS: These findings demonstrated that targeting TGF-β1 in combination with MK-2206 was the effective method for treatment of ATC.