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Article

Prolyl Hydroxylase 3 Knockdown Accelerates VHL-Mutant Kidney Cancer Growth In Vivo

1
Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2
Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
3
Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Ssang-Goo Cho
Int. J. Mol. Sci. 2021, 22(6), 2849; https://doi.org/10.3390/ijms22062849
Received: 22 February 2021 / Accepted: 7 March 2021 / Published: 11 March 2021
(This article belongs to the Section Molecular Oncology)
Von Hippel Lindau (VHL) inactivation, which is common in clear cell renal cell carcinoma (ccRCC), leads directly to the disruption of oxygen homoeostasis. VHL works through hypoxia-inducible factors (HIFs). Within this VHL-HIF system, prolyl hydroxylases (PHDs) are the intermediary proteins that initiate the degradation of HIFs. PHD isoform 3′s (PHD3) role in ccRCC growth in vivo is poorly understood. Using viral transduction, we knocked down the expression of PHD3 in the human ccRCC cell line UMRC3. Compared with control cells transduced with scrambled vector (UMRC3-SC cells), PHD3-knockdown cells (UMRC3-PHD3KD cells) showed increased cell invasion, tumor growth, and response to sunitinib. PHD3 knockdown reduced HIF2α expression and increased phosphorylated epidermal growth factor (EGFR) expression in untreated tumor models. However, following sunitinib treatment, expression of HIF2α and phosphorylated EGFR were equivalent in both PHD3 knockdown and control tumors. PHD3 knockdown changed the overall redox state of the cell as seen by the increased concentration of glutathione in PHD3 knockdown tumors relative to control tumors. UMRC3-PHD3KD cells had increased proliferation in cell culture when grown in the presence of hydrogen peroxide compared to UMRC3-SC control cells. Our findings illustrate (1) the variable effect of PHD3 on HIF2α expression, (2) an inverse relationship between PHD3 expression and tumor growth in ccRCC animal models, and (3) the role of PHD3 in maintaining the redox state of UMRC3 cells and their proliferative rate under oxidative stress. View Full-Text
Keywords: prolyl hydroxylases; renal cell carcinoma; hypoxia inducible factor 2α prolyl hydroxylases; renal cell carcinoma; hypoxia inducible factor 2α
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MDPI and ACS Style

Zacharias, N.M.; Wang, L.; Maity, T.; Li, L.; Millward, S.W.; Karam, J.A.; Wood, C.G.; Navai, N. Prolyl Hydroxylase 3 Knockdown Accelerates VHL-Mutant Kidney Cancer Growth In Vivo. Int. J. Mol. Sci. 2021, 22, 2849. https://doi.org/10.3390/ijms22062849

AMA Style

Zacharias NM, Wang L, Maity T, Li L, Millward SW, Karam JA, Wood CG, Navai N. Prolyl Hydroxylase 3 Knockdown Accelerates VHL-Mutant Kidney Cancer Growth In Vivo. International Journal of Molecular Sciences. 2021; 22(6):2849. https://doi.org/10.3390/ijms22062849

Chicago/Turabian Style

Zacharias, Niki M., Lei Wang, Tapati Maity, Li Li, Steven W. Millward, Jose A. Karam, Christopher G. Wood, and Neema Navai. 2021. "Prolyl Hydroxylase 3 Knockdown Accelerates VHL-Mutant Kidney Cancer Growth In Vivo" International Journal of Molecular Sciences 22, no. 6: 2849. https://doi.org/10.3390/ijms22062849

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