The non-apoptotic function of Caspase-8 in negatively regulating the CDK9-mediated Ser2 phosphorylation of RNA polymerase II in cervical cancer

• DOI: 10.1007/s00018-022-04598-3
• Publication Date: 2022-11-18T15:04:34Z
• Authors: Ranadip Mandal; Monika Raab; Franz Rödel; Andrea Krämer; Izabela Kostova; Samuel Peña-Llopis; Gioele Medici; Björn Häupl; Thomas Oellerich; Khayal Gasimli; Mourad Sanhaji; Sven Becker; Klaus Strebhardt
• Keywords: 0301 basic medicine; Caspase 8; 0303 health sciences; Medizin; Uterine Cervical Neoplasms; Cyclin-Dependent Kinase 9; 3. Good health; 03 medical and health sciences; Humans; Original Article; Female; RNA Polymerase II; Phosphorylation; Cisplatin; Protein Kinase Inhibitors

AbstractCervical cancer is the fourth most frequently diagnosed and fatal gynecological cancer. 15–61% of all cases metastasize and develop chemoresistance, reducing the 5-year survival of cervical cancer patients to as low as 17%. Therefore, unraveling the mechanisms contributing to metastasis is critical in developing better-targeted therapies against it. Here, we have identified a novel mechanism where nuclear Caspase-8 directly interacts with and inhibits the activity of CDK9, thereby modulating RNAPII-mediated global transcription, including those of cell-migration- and cell-invasion-associated genes. Crucially, low Caspase-8 expression in cervical cancer patients leads to poor prognosis, higher CDK9 phosphorylation at Thr186, and increased RNAPII activity in cervical cancer cell lines and patient biopsies. Caspase-8 knock-out cells were also more resistant to the small-molecule CDK9 inhibitor BAY1251152 in both 2D- and 3D-culture conditions. Combining BAY1251152 with Cisplatin synergistically overcame chemoresistance of Caspase-8-deficient cervical cancer cells. Therefore, Caspase-8 expression could be a marker in chemoresistant cervical tumors, suggesting CDK9 inhibitor treatment for their sensitization to Cisplatin-based chemotherapy.