Pevonedistat Suppresses Pancreatic Cancer Growth via Inactivation of the Neddylation Pathway
BackgroundThe neddylation pathway is aberrantly overactivated in multiple human cancers and has been indicated as an effective target for anticancer therapy in clinical trials. We aimed to study whether the neddylation pathway is upregulated in pancreatic cancer and whether pevonedistat, a first-in-...
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.822039/full |
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| author | Junfeng Xu Junfeng Xu Junfeng Xu Junfeng Xu Zheng Li Zheng Li Zheng Li Zheng Li Qifeng Zhuo Qifeng Zhuo Qifeng Zhuo Qifeng Zhuo Zeng Ye Zeng Ye Zeng Ye Zeng Ye Guixiong Fan Guixiong Fan Guixiong Fan Guixiong Fan Heli Gao Heli Gao Heli Gao Heli Gao Shunrong Ji Shunrong Ji Shunrong Ji Shunrong Ji Xianjun Yu Xianjun Yu Xianjun Yu Xianjun Yu Xiaowu Xu Xiaowu Xu Xiaowu Xu Xiaowu Xu Wensheng Liu Wensheng Liu Wensheng Liu Wensheng Liu Wenyan Xu Wenyan Xu Wenyan Xu Wenyan Xu |
| author_facet | Junfeng Xu Junfeng Xu Junfeng Xu Junfeng Xu Zheng Li Zheng Li Zheng Li Zheng Li Qifeng Zhuo Qifeng Zhuo Qifeng Zhuo Qifeng Zhuo Zeng Ye Zeng Ye Zeng Ye Zeng Ye Guixiong Fan Guixiong Fan Guixiong Fan Guixiong Fan Heli Gao Heli Gao Heli Gao Heli Gao Shunrong Ji Shunrong Ji Shunrong Ji Shunrong Ji Xianjun Yu Xianjun Yu Xianjun Yu Xianjun Yu Xiaowu Xu Xiaowu Xu Xiaowu Xu Xiaowu Xu Wensheng Liu Wensheng Liu Wensheng Liu Wensheng Liu Wenyan Xu Wenyan Xu Wenyan Xu Wenyan Xu |
| author_sort | Junfeng Xu |
| collection | DOAJ |
| description | BackgroundThe neddylation pathway is aberrantly overactivated in multiple human cancers and has been indicated as an effective target for anticancer therapy in clinical trials. We aimed to study whether the neddylation pathway is upregulated in pancreatic cancer and whether pevonedistat, a first-in-class anticancer agent specifically targeting this pathway, will suppress cancer tumorigenesis and progression.MethodsWe evaluated the expression pattern of neddylation pathway components in 179 pancreatic adenocarcinoma (PAAD) compared with 171 normal tissues from The Cancer Genome Atlas (TCGA) dataset and further assessed PAAD patient prognosis with high neddylation pathway expression via Gene Expression Profiling Interactive Analysis (GEPIA). We then analyzed malignant cancer phenotypes both in vitro and in vivo, as well as intrinsic molecular mechanisms upon pevonedistat treatment.ResultsWe found that the neddylation pathway was hyperactivated in pancreatic cancer. Patients with high neddylation pathway expression exhibited worse prognoses. Pevonedistat significantly inhibited the cancer cell cycle, cell growth, and proliferation; increased cell apoptosis; and decreased cancer cell xenografts in a mouse model. Mechanistically, pevonedistat treatment and the siRNA knockdown neddylation pathway were able to remarkably induce the accumulation of Wee1, p27, and p21. Further mechanistic studies revealed that pevonedistat mainly impaired the ubiquitination level and delayed the protein degradation of Wee1, p27, and p21.ConclusionsOur results showed that pevonedistat targeted the overexpression of the neddylation pathway in pancreatic cancer to induce cell growth suppression by inducing the accumulation of the cell cycle regulators Wee1, p27, and p21, which provides sound evidence for the clinical trial of pevonedistat for pancreatic cancer therapy. |
| first_indexed | 2024-04-11T18:10:56Z |
| format | Article |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-04-11T18:10:56Z |
| publishDate | 2022-01-01 |
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| series | Frontiers in Oncology |
| spelling | doaj.art-81daade9db07447da3a844a5e64af4002022-12-22T04:10:08ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-01-011210.3389/fonc.2022.822039822039Pevonedistat Suppresses Pancreatic Cancer Growth via Inactivation of the Neddylation PathwayJunfeng Xu0Junfeng Xu1Junfeng Xu2Junfeng Xu3Zheng Li4Zheng Li5Zheng Li6Zheng Li7Qifeng Zhuo8Qifeng Zhuo9Qifeng Zhuo10Qifeng Zhuo11Zeng Ye12Zeng Ye13Zeng Ye14Zeng Ye15Guixiong Fan16Guixiong Fan17Guixiong Fan18Guixiong Fan19Heli Gao20Heli Gao21Heli Gao22Heli Gao23Shunrong Ji24Shunrong Ji25Shunrong Ji26Shunrong Ji27Xianjun Yu28Xianjun Yu29Xianjun Yu30Xianjun Yu31Xiaowu Xu32Xiaowu Xu33Xiaowu Xu34Xiaowu Xu35Wensheng Liu36Wensheng Liu37Wensheng Liu38Wensheng Liu39Wenyan Xu40Wenyan Xu41Wenyan Xu42Wenyan Xu43Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaShanghai Pancreatic Cancer Institute, Shanghai, ChinaPancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaShanghai Pancreatic Cancer Institute, Shanghai, ChinaPancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaShanghai Pancreatic Cancer Institute, Shanghai, ChinaPancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaShanghai Pancreatic Cancer Institute, Shanghai, ChinaPancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaShanghai Pancreatic Cancer Institute, Shanghai, ChinaPancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaShanghai Pancreatic Cancer Institute, Shanghai, ChinaPancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaShanghai Pancreatic Cancer Institute, Shanghai, ChinaPancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaShanghai Pancreatic Cancer Institute, Shanghai, ChinaPancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaShanghai Pancreatic Cancer Institute, Shanghai, ChinaPancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaShanghai Pancreatic Cancer Institute, Shanghai, ChinaPancreatic Cancer Institute, Fudan University, Shanghai, ChinaDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, ChinaShanghai Pancreatic Cancer Institute, Shanghai, ChinaPancreatic Cancer Institute, Fudan University, Shanghai, ChinaBackgroundThe neddylation pathway is aberrantly overactivated in multiple human cancers and has been indicated as an effective target for anticancer therapy in clinical trials. We aimed to study whether the neddylation pathway is upregulated in pancreatic cancer and whether pevonedistat, a first-in-class anticancer agent specifically targeting this pathway, will suppress cancer tumorigenesis and progression.MethodsWe evaluated the expression pattern of neddylation pathway components in 179 pancreatic adenocarcinoma (PAAD) compared with 171 normal tissues from The Cancer Genome Atlas (TCGA) dataset and further assessed PAAD patient prognosis with high neddylation pathway expression via Gene Expression Profiling Interactive Analysis (GEPIA). We then analyzed malignant cancer phenotypes both in vitro and in vivo, as well as intrinsic molecular mechanisms upon pevonedistat treatment.ResultsWe found that the neddylation pathway was hyperactivated in pancreatic cancer. Patients with high neddylation pathway expression exhibited worse prognoses. Pevonedistat significantly inhibited the cancer cell cycle, cell growth, and proliferation; increased cell apoptosis; and decreased cancer cell xenografts in a mouse model. Mechanistically, pevonedistat treatment and the siRNA knockdown neddylation pathway were able to remarkably induce the accumulation of Wee1, p27, and p21. Further mechanistic studies revealed that pevonedistat mainly impaired the ubiquitination level and delayed the protein degradation of Wee1, p27, and p21.ConclusionsOur results showed that pevonedistat targeted the overexpression of the neddylation pathway in pancreatic cancer to induce cell growth suppression by inducing the accumulation of the cell cycle regulators Wee1, p27, and p21, which provides sound evidence for the clinical trial of pevonedistat for pancreatic cancer therapy.https://www.frontiersin.org/articles/10.3389/fonc.2022.822039/fullneddylation pathwaypevonedistatpancreatic cancer therapycell growthcell cycle |
| spellingShingle | Junfeng Xu Junfeng Xu Junfeng Xu Junfeng Xu Zheng Li Zheng Li Zheng Li Zheng Li Qifeng Zhuo Qifeng Zhuo Qifeng Zhuo Qifeng Zhuo Zeng Ye Zeng Ye Zeng Ye Zeng Ye Guixiong Fan Guixiong Fan Guixiong Fan Guixiong Fan Heli Gao Heli Gao Heli Gao Heli Gao Shunrong Ji Shunrong Ji Shunrong Ji Shunrong Ji Xianjun Yu Xianjun Yu Xianjun Yu Xianjun Yu Xiaowu Xu Xiaowu Xu Xiaowu Xu Xiaowu Xu Wensheng Liu Wensheng Liu Wensheng Liu Wensheng Liu Wenyan Xu Wenyan Xu Wenyan Xu Wenyan Xu Pevonedistat Suppresses Pancreatic Cancer Growth via Inactivation of the Neddylation Pathway Frontiers in Oncology neddylation pathway pevonedistat pancreatic cancer therapy cell growth cell cycle |
| title | Pevonedistat Suppresses Pancreatic Cancer Growth via Inactivation of the Neddylation Pathway |
| title_full | Pevonedistat Suppresses Pancreatic Cancer Growth via Inactivation of the Neddylation Pathway |
| title_fullStr | Pevonedistat Suppresses Pancreatic Cancer Growth via Inactivation of the Neddylation Pathway |
| title_full_unstemmed | Pevonedistat Suppresses Pancreatic Cancer Growth via Inactivation of the Neddylation Pathway |
| title_short | Pevonedistat Suppresses Pancreatic Cancer Growth via Inactivation of the Neddylation Pathway |
| title_sort | pevonedistat suppresses pancreatic cancer growth via inactivation of the neddylation pathway |
| topic | neddylation pathway pevonedistat pancreatic cancer therapy cell growth cell cycle |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.822039/full |
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