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Targeting the WEE1 kinase strengthens the antitumor activity of imatinib via promoting KIT autophagic degradation in gastrointestinal stromal tumors.

Abstract

BACKGROUND

Activating mutation of KIT or PDGFRA is the primary molecular mechanism for gastrointestinal stromal tumors (GISTs). Although imatinib has a revolutionary effect on GIST therapeutics, the benefits are not durable. Increasing reports have demonstrated that cell cycle checkpoint plays critical roles in GIST. Here, we explore the role of WEE1 kinase in GIST progression.

METHODS

Oncomine public database, western blotting, and immunohistochemistry were used to analyze WEE1 expression in GISTs. Using MTT assays, colony formation analysis, and flow cytometry, we examined the role of WEE1 in GIST cells and the antitumor activity of the inhibitor MK1775 alone, or in combination with imatinib. Cycloheximide chase assay and pharmacological inhibition of autophagy and proteasome pathway were performed to analyze KIT expression. Additionally, autophagic markers Beclin1 and LC3B were detected by western blotting.

RESULTS

Upregulated WEE1 expression was observed in GIST tissues and correlated with tumor size, mitotic count, and risk grade. Inhibition of WEE1 significantly suppressed GIST cell proliferation, induced apoptosis and cell cycle arrest. Imatinib and MK1775 co-treatment markedly enhanced the antitumor activity. Targeting WEE1 decreased the expression of KIT expression. Moreover, WEE1 stabilized KIT protein and KIT reduction observed upon WEE1 inhibition could be reversed by pharmacological inhibition of autophagy, but not proteasome pathway. WEE1 inhibition also increased Beclin1 expression and LC3B II/I ratio in GIST cells.

CONCLUSIONS

Our data suggest that WEE1 plays a pivotal role in GIST proliferation. WEE1 inhibition could promote KIT autophagic degradation and, therefore, targeting WEE1 might represent a novel strategy for GIST therapies.

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  • Authors+Show Affiliations

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    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

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    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

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    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

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    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

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    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

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    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

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    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

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    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

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    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

    Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. zhangpengwh@hust.edu.cn.

    Source

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31197522

    Citation

    Liu, Weizhen, et al. "Targeting the WEE1 Kinase Strengthens the Antitumor Activity of Imatinib Via Promoting KIT Autophagic Degradation in Gastrointestinal Stromal Tumors." Gastric Cancer : Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 2019.
    Liu W, Zeng X, Yin Y, et al. Targeting the WEE1 kinase strengthens the antitumor activity of imatinib via promoting KIT autophagic degradation in gastrointestinal stromal tumors. Gastric Cancer. 2019.
    Liu, W., Zeng, X., Yin, Y., Li, C., Yang, W., Wan, W., ... Zhang, P. (2019). Targeting the WEE1 kinase strengthens the antitumor activity of imatinib via promoting KIT autophagic degradation in gastrointestinal stromal tumors. Gastric Cancer : Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, doi:10.1007/s10120-019-00977-1.
    Liu W, et al. Targeting the WEE1 Kinase Strengthens the Antitumor Activity of Imatinib Via Promoting KIT Autophagic Degradation in Gastrointestinal Stromal Tumors. Gastric Cancer. 2019 Jun 13; PubMed PMID: 31197522.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Targeting the WEE1 kinase strengthens the antitumor activity of imatinib via promoting KIT autophagic degradation in gastrointestinal stromal tumors. AU - Liu,Weizhen, AU - Zeng,Xiangyu, AU - Yin,Yuping, AU - Li,Chengguo, AU - Yang,Wenchang, AU - Wan,Wenze, AU - Shi,Liang, AU - Wang,Guobin, AU - Tao,Kaixiong, AU - Zhang,Peng, Y1 - 2019/06/13/ PY - 2018/11/10/received PY - 2019/06/04/accepted PY - 2019/6/15/entrez KW - Antitumor KW - Autophagic degradation KW - Gastrointestinal stromal tumors KW - MK1775 KW - WEE1 JF - Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association JO - Gastric Cancer N2 - BACKGROUND: Activating mutation of KIT or PDGFRA is the primary molecular mechanism for gastrointestinal stromal tumors (GISTs). Although imatinib has a revolutionary effect on GIST therapeutics, the benefits are not durable. Increasing reports have demonstrated that cell cycle checkpoint plays critical roles in GIST. Here, we explore the role of WEE1 kinase in GIST progression. METHODS: Oncomine public database, western blotting, and immunohistochemistry were used to analyze WEE1 expression in GISTs. Using MTT assays, colony formation analysis, and flow cytometry, we examined the role of WEE1 in GIST cells and the antitumor activity of the inhibitor MK1775 alone, or in combination with imatinib. Cycloheximide chase assay and pharmacological inhibition of autophagy and proteasome pathway were performed to analyze KIT expression. Additionally, autophagic markers Beclin1 and LC3B were detected by western blotting. RESULTS: Upregulated WEE1 expression was observed in GIST tissues and correlated with tumor size, mitotic count, and risk grade. Inhibition of WEE1 significantly suppressed GIST cell proliferation, induced apoptosis and cell cycle arrest. Imatinib and MK1775 co-treatment markedly enhanced the antitumor activity. Targeting WEE1 decreased the expression of KIT expression. Moreover, WEE1 stabilized KIT protein and KIT reduction observed upon WEE1 inhibition could be reversed by pharmacological inhibition of autophagy, but not proteasome pathway. WEE1 inhibition also increased Beclin1 expression and LC3B II/I ratio in GIST cells. CONCLUSIONS: Our data suggest that WEE1 plays a pivotal role in GIST proliferation. WEE1 inhibition could promote KIT autophagic degradation and, therefore, targeting WEE1 might represent a novel strategy for GIST therapies. SN - 1436-3305 UR - https://www.unboundmedicine.com/medline/citation/31197522/Targeting_the_WEE1_kinase_strengthens_the_antitumor_activity_of_imatinib_via_promoting_KIT_autophagic_degradation_in_gastrointestinal_stromal_tumors L2 - http://dx.doi.org/10.1007/s10120-019-00977-1 DB - PRIME DP - Unbound Medicine ER -