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CDK12 is a promising therapeutic target for the transcription cycle and DNA damage response in metastatic osteosarcoma.
Li, Zihao; Li, Xiaoyang; Seebacher, Nicole A; Liu, Xu; Wu, Wence; Yu, Shengji; Hornicek, Francis J; Huang, Changzhi; Duan, Zhenfeng.
Afiliación
  • Li Z; Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 10021China.
  • Li X; Department of Orthopedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 10021China.
  • Seebacher NA; Department of Oncology, University of Oxford OX3 9DU, Oxford, UK.
  • Liu X; St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
  • Wu W; Department of Orthopedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 10021China.
  • Yu S; Department of Orthopedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 10021China.
  • Hornicek FJ; Department of Orthopedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 10021China.
  • Huang C; Sarcoma Biology Laboratory, Department of Orthopaedics, Sylvester Comprehensive Cancer Center, and the University of Miami Miller School of Medicine, Miami, FL, 33136USA.
  • Duan Z; Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 10021China.
Carcinogenesis ; 45(10): 786-798, 2024 Oct 10.
Article en En | MEDLINE | ID: mdl-39082894
ABSTRACT
Osteosarcoma (OS) is a bone malignant tumor affecting children, adolescents, and young adults. Currently, osteosarcoma is treated with chemotherapy regimens established over 40 years ago. The investigation of novel therapeutic strategies for the treatment of osteosarcoma remains an important clinical need. Cyclin-dependent kinases (CDKs) have been considered promising molecular targets in cancer therapy. Among these, CDK12 has been shown to play a crucial role in the pathogenesis of malignancies, but its clinical significance and biological mechanisms in osteosarcoma remain unclear. In the present study, we aim to determine the expression and function of CDK12 and evaluate its prognostic and therapeutic value in metastatic osteosarcoma. We found that overexpression of CDK12 was associated with high tumor grade, tumor progression and reduced patient survival. The underlying mechanism revealed that knockdown of CDK12 expression with small interfering RNA or functional inhibition with the CDK12-targeting agent THZ531 effectively exhibited time- and dose-dependent cytotoxicity. Downregulation of CDK12 paused transcription by reducing RNAP II phosphorylation, interfered with DNA damage repair with increased γH2AX, and decreased cell proliferation through the PI3K-AKT pathway. This was accompanied by the promotion of apoptosis, as evidenced by enhanced Bax expression and reduced Bcl-xL expression. Furthermore, the CDK12 selective inhibitor THZ531 also hindered ex vivo 3D spheroid formation, growth of in vitro 2D cell colony, and prevented cell mobility. Our findings highlight the clinical importance of CDK12 as a potentially valuable prognostic biomarker and therapeutic target in metastatic osteosarcoma.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Óseas / Daño del ADN / Osteosarcoma / Apoptosis / Quinasas Ciclina-Dependientes / Proliferación Celular Límite: Adolescent / Animals / Female / Humans / Male Idioma: En Revista: Carcinogenesis Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Óseas / Daño del ADN / Osteosarcoma / Apoptosis / Quinasas Ciclina-Dependientes / Proliferación Celular Límite: Adolescent / Animals / Female / Humans / Male Idioma: En Revista: Carcinogenesis Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido