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Nobiletin downregulates the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma

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...

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Autores principales: Chen, Tingting, Liu, Liu, Zou, Yonghong, Hu, Xiaoyan, Zhang, Wenfeng, Zhou, Tao, Luo, Xi, Fu, Weihua, Xu, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Compuscript 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877181/
https://www.ncbi.nlm.nih.gov/pubmed/33628597
http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0186
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author Chen, Tingting
Liu, Liu
Zou, Yonghong
Hu, Xiaoyan
Zhang, Wenfeng
Zhou, Tao
Luo, Xi
Fu, Weihua
Xu, Jie
author_facet Chen, Tingting
Liu, Liu
Zou, Yonghong
Hu, Xiaoyan
Zhang, Wenfeng
Zhou, Tao
Luo, Xi
Fu, Weihua
Xu, Jie
author_sort Chen, Tingting
collection PubMed
description 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.
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spelling pubmed-78771812021-02-23 Nobiletin downregulates the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma Chen, Tingting Liu, Liu Zou, Yonghong Hu, Xiaoyan Zhang, Wenfeng Zhou, Tao Luo, Xi Fu, Weihua Xu, Jie Cancer Biol Med Original Article 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. Compuscript 2021-02-15 2021-02-15 /pmc/articles/PMC7877181/ /pubmed/33628597 http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0186 Text en Copyright: © 2021, Cancer Biology & Medicine https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY) 4.0 (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
spellingShingle Original Article
Chen, Tingting
Liu, Liu
Zou, Yonghong
Hu, Xiaoyan
Zhang, Wenfeng
Zhou, Tao
Luo, Xi
Fu, Weihua
Xu, Jie
Nobiletin downregulates the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma
title Nobiletin downregulates the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma
title_full Nobiletin downregulates the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma
title_fullStr Nobiletin downregulates the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma
title_full_unstemmed Nobiletin downregulates the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma
title_short Nobiletin downregulates the SKP2-p21/p27-CDK2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma
title_sort nobiletin downregulates the skp2-p21/p27-cdk2 axis to inhibit tumor progression and shows synergistic effects with palbociclib on renal cell carcinoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877181/
https://www.ncbi.nlm.nih.gov/pubmed/33628597
http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0186
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