Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1783650116987518976 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7877181 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Compuscript |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT chentingting nobiletindownregulatestheskp2p21p27cdk2axistoinhibittumorprogressionandshowssynergisticeffectswithpalbociclibonrenalcellcarcinoma AT liuliu nobiletindownregulatestheskp2p21p27cdk2axistoinhibittumorprogressionandshowssynergisticeffectswithpalbociclibonrenalcellcarcinoma AT zouyonghong nobiletindownregulatestheskp2p21p27cdk2axistoinhibittumorprogressionandshowssynergisticeffectswithpalbociclibonrenalcellcarcinoma AT huxiaoyan nobiletindownregulatestheskp2p21p27cdk2axistoinhibittumorprogressionandshowssynergisticeffectswithpalbociclibonrenalcellcarcinoma AT zhangwenfeng nobiletindownregulatestheskp2p21p27cdk2axistoinhibittumorprogressionandshowssynergisticeffectswithpalbociclibonrenalcellcarcinoma AT zhoutao nobiletindownregulatestheskp2p21p27cdk2axistoinhibittumorprogressionandshowssynergisticeffectswithpalbociclibonrenalcellcarcinoma AT luoxi nobiletindownregulatestheskp2p21p27cdk2axistoinhibittumorprogressionandshowssynergisticeffectswithpalbociclibonrenalcellcarcinoma AT fuweihua nobiletindownregulatestheskp2p21p27cdk2axistoinhibittumorprogressionandshowssynergisticeffectswithpalbociclibonrenalcellcarcinoma AT xujie nobiletindownregulatestheskp2p21p27cdk2axistoinhibittumorprogressionandshowssynergisticeffectswithpalbociclibonrenalcellcarcinoma |