PURPOSE: We determined the frequency of mTOR/p70S6 kinase signaling pathway activation in clear cell renal cell carcinoma. MATERIALS AND METHODS: Phospho-S6 (Ser235/236) and phospho-mTOR (Ser2448) staining was performed on renal tumor tissue microarrays containing 29 clear cell renal cell carcinomas. Mutational analysis of Rheb and RhebL1 was performed on DNA from phospho-mTOR/phospho-S6 positive clear cell renal cell carcinoma. The 3 clear cell renal cell carcinoma derived cell lines A498, 786-O and Caki1 were also assessed for mTOR activation and the effect of the mTOR inhibitor rapamycin (Biomol) on proliferation. RESULTS: Moderate or strong phospho-S6 immunoreactivity was found in 17 of 29 clear cell carcinomas (59%), of which 14 were also moderately/strongly positive for phospho-mTOR (Ser2448). We hypothesized that this activation of the mTOR signaling pathway in clear cell renal cell carcinoma could reflect mutational activation of Rheb or RhebL1, which are Ras family members that directly activate mTOR. However, no mutations in exons 3 and 4 (homologous sites of Ras activating mutations) in Rheb or RhebL1 were identified. Two of 3 renal clear cell carcinoma derived cell lines also showed inappropriate S6 hyperphosphorylation. Treatment of all 3 cell lines with rapamycin significantly decreased S6 phosphorylation and proliferation. CONCLUSIONS: The mTOR/p70S6 kinase signaling pathway is activated in most clear cell renal cell carcinomas. Moreover, the growth of renal clear cell carcinoma derived cell lines is inhibited by rapamycin. This is especially significant in light of new agents such as CCI-779, an ester of rapamycin and inhibitor of mTOR, which has shown promise in the treatment of renal carcinoma.
PURPOSE: We determined the frequency of mTOR/p70S6 kinase signaling pathway activation in clear cell renal cell carcinoma. MATERIALS AND METHODS: Phospho-S6 (Ser235/236) and phospho-mTOR (Ser2448) staining was performed on renal tumor tissue microarrays containing 29 clear cell renal cell carcinomas. Mutational analysis of Rheb and RhebL1 was performed on DNA from phospho-mTOR/phospho-S6 positive clear cell renal cell carcinoma. The 3 clear cell renal cell carcinoma derived cell lines A498, 786-O and Caki1 were also assessed for mTOR activation and the effect of the mTOR inhibitor rapamycin (Biomol) on proliferation. RESULTS: Moderate or strong phospho-S6 immunoreactivity was found in 17 of 29 clear cell carcinomas (59%), of which 14 were also moderately/strongly positive for phospho-mTOR (Ser2448). We hypothesized that this activation of the mTOR signaling pathway in clear cell renal cell carcinoma could reflect mutational activation of Rheb or RhebL1, which are Ras family members that directly activate mTOR. However, no mutations in exons 3 and 4 (homologous sites of Ras activating mutations) in Rheb or RhebL1 were identified. Two of 3 renal clear cell carcinoma derived cell lines also showed inappropriate S6 hyperphosphorylation. Treatment of all 3 cell lines with rapamycin significantly decreased S6 phosphorylation and proliferation. CONCLUSIONS: The mTOR/p70S6 kinase signaling pathway is activated in most clear cell renal cell carcinomas. Moreover, the growth of renal clear cell carcinoma derived cell lines is inhibited by rapamycin. This is especially significant in light of new agents such as CCI-779, an ester of rapamycin and inhibitor of mTOR, which has shown promise in the treatment of renal carcinoma.
Authors: Boyi Gan; Carol Lim; Gerald Chu; Sujun Hua; Zhihu Ding; Michael Collins; Jian Hu; Shan Jiang; Eliot Fletcher-Sananikone; Li Zhuang; Michelle Chang; Hongwu Zheng; Y Alan Wang; David J Kwiatkowski; William G Kaelin; Sabina Signoretti; Ronald A DePinho Journal: Cancer Cell Date: 2010-11-16 Impact factor: 31.743
Authors: Nir Kleinmann; Wilhelmina C M Duivenvoorden; Sarah N Hopmans; Laura K Beatty; Shengjun Qiao; Daniel Gallino; Sarka Lhotak; Dean Daya; Athanasios Paschos; Richard C Austin; Jehonathan H Pinthus Journal: Clin Exp Metastasis Date: 2013-10-05 Impact factor: 5.150
Authors: Guoqiang Li; Weimin Ci; Subhradip Karmakar; Ke Chen; Ruby Dhar; Zhixiang Fan; Zhongqiang Guo; Jing Zhang; Yuwen Ke; Lu Wang; Min Zhuang; Shengdi Hu; Xuesong Li; Liqun Zhou; Xianghong Li; Matthew F Calabrese; Edmond R Watson; Sandip M Prasad; Carrie Rinker-Schaeffer; Scott E Eggener; Thomas Stricker; Yong Tian; Brenda A Schulman; Jiang Liu; Kevin P White Journal: Cancer Cell Date: 2014-03-20 Impact factor: 31.743
Authors: Eva Juengel; Johanna Engler; Iyad Natsheh; Jon Jones; Ausra Mickuckyte; Lukasz Hudak; Dietger Jonas; Roman A Blaheta Journal: BMC Cancer Date: 2009-05-27 Impact factor: 4.430