Tingting Chen1, Liu Liu2, Yonghong Zou3, Xiaoyan Hu1, Wenfeng Zhang4, Tao Zhou1, Xi Luo5, Weihua Fu1, Jie Xu1. 1. Department of Urology, Xinqiao Hospital of Army Medical University, Chongqing 400037, China. 2. Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430040, China. 3. Department of Reproductive Medicine, Ji'an Central People's Hospital, Ji'an 343100, China. 4. Department of Infectious Disease, the First Affiliated Hospital, Nanchang University, Nanchang 330001, China. 5. Department of Oncology, Southwest Hospital of Army Medical University, Chongqing 400038, China.
Abstract
Objective: Natural extracts, including nobiletin, have been reported to enhance the efficacy and sensitivity of chemotherapeutic drugs. However, whether and how nobiletin affects tumor growth and progression in renal cell carcinoma (RCC) are still unclear. Methods: Cell proliferation, cell cycle and apoptosis analyses, colony-formation assays, immunoblotting analysis, and qRT-PCR analysis were performed to investigate how nobiletin affected RCC cell proliferation in vitro. The nude mouse model was used to test the efficacy of nobiletin alone or in combination with palbociclib. Results: Nobiletin inhibited cell proliferation by inducing G1 cell cycle arrest and cell apoptosis in RCC cells. Mechanistically, nobiletin decreased SKP2 protein expression by reducing its transcriptional level. The downregulated SKP2 caused accumulation of its substrates, p27 and p21, which further inhibited the activity of the G1 phase-related protein, CDK2, leading to inhibition of cell proliferation and tumor formation. A higher SKP2 protein level indicated less sensitivity to the CDK4/6 inhibitor, palbociclib. A combination of nobiletin and palbociclib showed a synergistic tumor inhibition in vitro and in an in vivo model. Conclusions: Nobiletin downregulated the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and showed synergistic tumor inhibition effects with the CDK4/6 inhibitor, palbociclib, on RCC, which indicates a potential new therapeutic strategy. Copyright:
Objective: Natural extracts, including nobiletin, have been reported to enhance the efficacy and sensitivity of chemotherapeutic drugs. However, whether and how nobiletin affects tumor growth and progression in renal cell carcinoma (RCC) are still unclear. Methods: Cell proliferation, cell cycle and apoptosis analyses, colony-formation assays, immunoblotting analysis, and qRT-PCR analysis were performed to investigate how nobiletin affected RCC cell proliferation in vitro. The nude mouse model was used to test the efficacy of nobiletin alone or in combination with palbociclib. Results: Nobiletin inhibited cell proliferation by inducing G1 cell cycle arrest and cell apoptosis in RCC cells. Mechanistically, nobiletin decreased SKP2 protein expression by reducing its transcriptional level. The downregulated SKP2 caused accumulation of its substrates, p27 and p21, which further inhibited the activity of the G1 phase-related protein, CDK2, leading to inhibition of cell proliferation and tumor formation. A higher SKP2 protein level indicated less sensitivity to the CDK4/6 inhibitor, palbociclib. A combination of nobiletin and palbociclib showed a synergistic tumor inhibition in vitro and in an in vivo model. Conclusions: Nobiletin downregulated the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and showed synergistic tumor inhibition effects with the CDK4/6 inhibitor, palbociclib, on RCC, which indicates a potential new therapeutic strategy. Copyright:
Authors: J Wu; S-W Lee; X Zhang; F Han; S-Y Kwan; X Yuan; W-L Yang; Y S Jeong; A H Rezaeian; Y Gao; Y-X Zeng; H-K Lin Journal: Oncogene Date: 2012-02-06 Impact factor: 9.867
Authors: Qing Chen; Weilin Xie; Deborah J Kuhn; Peter M Voorhees; Antonia Lopez-Girona; Derek Mendy; Laura G Corral; Veronique Plantevin Krenitsky; Weiming Xu; Laure Moutouh-de Parseval; David R Webb; Frank Mercurio; Keiichi I Nakayama; Keiko Nakayama; Robert Z Orlowski Journal: Blood Date: 2008-02-27 Impact factor: 22.113