TY - JOUR
T1 - 2′-Hydroxyflavanone inhibits proliferation, tumor vascularization and promotes normal differentiation in VHL-mutant renal cell carcinoma
AU - Nagaprashantha, Lokesh Dalasanur
AU - Vatsyayan, Rit
AU - Singhal, Jyotsana
AU - Lelsani, Poorna
AU - Prokai, Laszlo
AU - Awasthi, Sanjay
AU - Singhal, Sharad S.
N1 - Funding Information:
This work was supported by the National Institutes of Health grant (CA 77495 to S.A. & S.S.S.) and ISIORR018999-01A1; the Welch Foundation endowment (BK-0031 to L.P.); the Cancer Research Foundation of North Texas; Institute for Cancer Research & the Joe & Jessie Crump Fund for Medical Education to S.S.S.
Funding Information:
The authors thank Dr Xiangle Sun, core facility at the University of North Texas Health Science Center, Fort Worth, TX, for helping with flow cytometry and laser capture microdissection (supported by NIH Grant ISIORR018999-01A1). We also thank Dr Sumihiro Suzuki, Department of Biostatistics, School of Public Health, University of North Texas Health Science Center, Fort Worth, TX, for his assistance in the statistical analyses of the data.
PY - 2011/4
Y1 - 2011/4
N2 - Renal cell carcinoma (RCC) is one of the top ten cancers prevalent in USA. Loss-of-function mutations in the von Hippel-Lindau (VHL) gene constitute an established risk factor contributing to 75% of total reported cases of RCC. Loss-of-VHL leads to a highly vascularized phenotype of renal tumors. Intake of citrus fruits has been proven to reduce the risk of RCC in multicenter international studies. Hence, we studied the effect of 2′-hydroxyflavanone (2HF), an active anticancer compound from oranges, in RCC. Our in vitro investigations revealed that 2HF suppresses VHL-mutant RCC to a significantly greater extent than VHL-wild-type RCC by inhibiting epidermal growth factor receptor signaling, which is increased due to VHL mutations in RCC. Our results also revealed for the first time, that 2HF inhibits glutathione S-transferase pi activity. 2HF reduced cyclin B1 and CDK4 levels and induced G2/M phase arrest in VHL-mutant RCC. Importantly, 2HF inhibited the angiogenesis in VHL-mutant RCC by decreasing vascular endothelial growth factor expression. Our in vivo studies in mice xenografts confirmed our in vitro results as evident by decreased levels of proliferation marker, Ki67 and angiogenic marker, CD31, in 2HF-treated mice xenografts of VHL-mutant RCC. 2HF also increased the expression of E-cadherin in VHL-mutant RCC, which would be of significance in restoring normal epithelial phenotype. Collectively, our in vitro and in vivo results revealed the potent antiproliferative, antiangiogenic and prodifferentiation properties of 2HF in VHL-mutant RCC, sparing normal cells, which could have significant implications not only in the specific management of VHL-mutant RCC but also towards other VHL syndromes.
AB - Renal cell carcinoma (RCC) is one of the top ten cancers prevalent in USA. Loss-of-function mutations in the von Hippel-Lindau (VHL) gene constitute an established risk factor contributing to 75% of total reported cases of RCC. Loss-of-VHL leads to a highly vascularized phenotype of renal tumors. Intake of citrus fruits has been proven to reduce the risk of RCC in multicenter international studies. Hence, we studied the effect of 2′-hydroxyflavanone (2HF), an active anticancer compound from oranges, in RCC. Our in vitro investigations revealed that 2HF suppresses VHL-mutant RCC to a significantly greater extent than VHL-wild-type RCC by inhibiting epidermal growth factor receptor signaling, which is increased due to VHL mutations in RCC. Our results also revealed for the first time, that 2HF inhibits glutathione S-transferase pi activity. 2HF reduced cyclin B1 and CDK4 levels and induced G2/M phase arrest in VHL-mutant RCC. Importantly, 2HF inhibited the angiogenesis in VHL-mutant RCC by decreasing vascular endothelial growth factor expression. Our in vivo studies in mice xenografts confirmed our in vitro results as evident by decreased levels of proliferation marker, Ki67 and angiogenic marker, CD31, in 2HF-treated mice xenografts of VHL-mutant RCC. 2HF also increased the expression of E-cadherin in VHL-mutant RCC, which would be of significance in restoring normal epithelial phenotype. Collectively, our in vitro and in vivo results revealed the potent antiproliferative, antiangiogenic and prodifferentiation properties of 2HF in VHL-mutant RCC, sparing normal cells, which could have significant implications not only in the specific management of VHL-mutant RCC but also towards other VHL syndromes.
UR - http://www.scopus.com/inward/record.url?scp=79953682228&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgr021
DO - 10.1093/carcin/bgr021
M3 - Article
C2 - 21304051
AN - SCOPUS:79953682228
SN - 0143-3334
VL - 32
SP - 568
EP - 575
JO - Carcinogenesis
JF - Carcinogenesis
IS - 4
ER -