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KMID : 0620920220540070999
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Experimental & Molecular Medicine
2022 Volume.54 No. 7 p.999 ~ p.1010
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PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer
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Ma Hanlin
Qi Gonghua
Han Fang
Peng Jiali
Yuan Cunzhong
Kong Beihua
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Abstract
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Resistance to PARP inhibitors (PARPi) remains a therapeutic challenge in ovarian cancer patients. PDZ-binding kinase (PBK) participates in the chemoresistance of many malignancies. However, the role of PBK in PARPi resistance of ovarian cancer is obscure. In the current study, we demonstrated that overexpression of PBK contributed to olaparib resistance in ovarian cancer cells. Knockdown of PBK sensitized olaparib-resistant SKOV3 cells to olaparib. Inhibition of PBK using a specific inhibitor enhanced the therapeutic efficiency of olaparib. Mechanically, PBK directly interacted with TRIM37 to promote its phosphorylation and nuclear translocation. which subsequently activates the NFκB pathway. Additionally, PBK enhanced olaparib resistance of ovarian cancer by regulating the NFκB/TRIM37 axis in vitro and in vivo. In conclusion, PBK confers ovarian cancer resistance to PARPi through activating the TRIM37-mediated NFκB pathway, and targeted inhibition of PBK provided the new therapy to improve PARPi treatment outcomes for ovarian cancer patients.
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KEYWORD
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Cancer therapeutic resistance, Mechanisms of disease, Ovarian cancer, Translational research
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