Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 79, Issue 12, Pages -Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-022-04598-3
Keywords
Caspase-8; Non-apoptotic function; Transcription; CDK9; P-TEFb; RNAPII
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [MA 9266/2-1]
- Deutsche Krebshilfe [70114007]
- German Cancer Consortium (DKTK, Heidelberg)
- Projekt DEAL
Ask authors/readers for more resources
This study identifies a new mechanism where nuclear Caspase-8 inhibits the activity of CDK9, leading to poor prognosis and chemoresistance in cervical cancer. Caspase-8-deficient cervical cancer cells show increased resistance to CDK9 inhibitors, but combination with Cisplatin can synergistically overcome this resistance.
Cervical 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available