Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF-κB and JNK dependent manner
Jiabin An1, Yanchuan Guo2, Ting Wang1, Allan J. Pantuck3, Matthew B. Rettig1,3,4
1. Department of Medicine, Division of Hematology-Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA;
2. Technical Institute of Physics and Chemistry, Chinese Academy of Science, Beijing, 100190, China;
3. Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA;
4. Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF-κB and JNK dependent manner
Jiabin An1, Yanchuan Guo2, Ting Wang1, Allan J. Pantuck3, Matthew B. Rettig1,3,4
1. Department of Medicine, Division of Hematology-Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA;
2. Technical Institute of Physics and Chemistry, Chinese Academy of Science, Beijing, 100190, China;
3. Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA;
4. Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
摘要 Objective: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) and is characterized by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. One effect of VHL inactivation is hypoxia inducible factor alpha (HIFα)-independent constitutive activation of nuclear factor kappa B (NF-κB) and c-jun N-terminal kinase (JNK). Both NF-κB and JNK drive ccRCC growth and epithelial to mesenchymal transition (EMT). The purpose of this study was to determine the biochemical effects of pomegranate juice extracts (PE) on RCC cell lines. Methods: The pre-clinical effects of PE on NF-κB, JNK, and the EMT phenotype were assayed, including its effect on proliferation, anchorage-independent growth, and invasion of pVHLdeficient RCCs. Results: PE inhibits the NF-κB and JNK pathways and consequently inhibits the EMT phenotype of pVHL-deficient ccRCCs. The effects of PE are concentration-dependent and affect not only biochemical markers of EMT (i.e., cadherin expression) but also functional manifestations of EMT, such as invasion. These effects are manifested within days of exposure to PE when diluted 2000-fold. Highly dilute concentrations of PE (106 dilution), which do not impact these pathways in the short term, were found to have NF-κB and JNK inhibitory effects and ability to reverse the EMT phenotype following prolonged exposure. Conclusion: These findings suggest that PE may mediate inhibition growth of pVHL-deficient ccRCCs and raises the possibility of its use as a dietary adjunct to managing patients with active surveillance for small, localized, incidentally identified renal tumors so as to avoid more invasive procedures such as nephrectomy.
Abstract: Objective: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) and is characterized by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. One effect of VHL inactivation is hypoxia inducible factor alpha (HIFα)-independent constitutive activation of nuclear factor kappa B (NF-κB) and c-jun N-terminal kinase (JNK). Both NF-κB and JNK drive ccRCC growth and epithelial to mesenchymal transition (EMT). The purpose of this study was to determine the biochemical effects of pomegranate juice extracts (PE) on RCC cell lines. Methods: The pre-clinical effects of PE on NF-κB, JNK, and the EMT phenotype were assayed, including its effect on proliferation, anchorage-independent growth, and invasion of pVHLdeficient RCCs. Results: PE inhibits the NF-κB and JNK pathways and consequently inhibits the EMT phenotype of pVHL-deficient ccRCCs. The effects of PE are concentration-dependent and affect not only biochemical markers of EMT (i.e., cadherin expression) but also functional manifestations of EMT, such as invasion. These effects are manifested within days of exposure to PE when diluted 2000-fold. Highly dilute concentrations of PE (106 dilution), which do not impact these pathways in the short term, were found to have NF-κB and JNK inhibitory effects and ability to reverse the EMT phenotype following prolonged exposure. Conclusion: These findings suggest that PE may mediate inhibition growth of pVHL-deficient ccRCCs and raises the possibility of its use as a dietary adjunct to managing patients with active surveillance for small, localized, incidentally identified renal tumors so as to avoid more invasive procedures such as nephrectomy.
基金资助: This work was supported by a Merit Review grant (M.B.R.) from the Department of Veterans Affairs and by an unrestricted research grant Pom Wonderful (A.P.).
引用本文:
Jiabin An, Yanchuan Guo, Ting Wang, Allan J. Pantuck, Matthew B. Rettig. Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF-κB and JNK dependent manner[J]. Asian Journal of Urology, 2015, 2(1): 38-45.
Jiabin An, Yanchuan Guo, Ting Wang, Allan J. Pantuck, Matthew B. Rettig. Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF-κB and JNK dependent manner. Asian Journal of Urology, 2015, 2(1): 38-45.
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