Elevation of effective p53 expression sensitizes wild-type p53 breast cancer cells to CDK7 inhibitor THZ1.

Abstract

BACKGROUND:

The cyclin-dependent kinase 7 (CDK7) inhibitor THZ1 represses multiple cancer cells. However, its tumor-repressive efficiency in wild-type p53 breast cancer cells remains controversial.

METHODS:

We conducted various assays, including CCK8, colony formation, flow cytometry, western blotting, and lactate dehydrogenase release detection, to clarify whether p53 elevation sensitizes breast cancer cells to THZ1.

RESULTS:

We found that upregulating functional p53 contributes to the increased sensitivity of breast cancer cells to THZ1. Increased THZ1 sensitivity requires active p53 and an intact p53 pathway, which was confirmed by introducing exogenous wild-type p53 and the subsequent elevation of THZ1-mediated tumor suppression in breast cancer cells carrying mutant p53. We confirmed that p53 accumulates in the nucleus and mitochondria during cell death. Furthermore, we identified extensive transcriptional disruption, rather than solely CDK7 inhibition, as the mechanism underlying the nutlin-3 and THZ1-induced death of breast cancer cells. Finally, we observed the combined nutlin-3 and THZ1 treatment amplified gasdermin E cleavage.

CONCLUSION:

Enhanced sensitivity of breast cancer cells to THZ1 can be achieved by increasing effective p53 expression. Our approach may serve as a potential treatment for patients with breast cancer resistant to regular therapies. Video Abstract.

• Authors: Yueyuan Wang, Zhihao Zhang, Xuguang Mi, Mingxi Li, Dan Huang, Tingting Song, Xiaoyan Qi, Ming Yang
• Journal: Cell communication and signaling : CCS (Cell Commun Signal) Vol. 20 Issue 1 Pg. 96 (09 05 2022) ISSN: 1478-811X [Electronic] England
• PMID: 36058938 (Publication Type: Journal Article, Video-Audio Media, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Phenylenediamines
• Protein Kinase Inhibitors
• Pyrimidines
• Tumor Suppressor Protein p53

Topics

• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Phenylenediamines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Tumor Suppressor Protein p53 (metabolism)