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Galeterone sensitizes breast cancer to chemotherapy via targeting MNK/eIF4E and β-catenin.
- Source :
-
Cancer Chemotherapy & Pharmacology . 2021, Vol. 87 Issue 1, p85-93. 9p. - Publication Year :
- 2021
-
Abstract
- Aberrant activation of eIF4E signalling pathway is common in breast cancer and holds potential therapeutic options. In our work, galeterone as a chemical compound under clinical trials for the treatment of prostate cancer, was identified to be effective in targeting breast cancer cells via suppressing MNK-eIF4E and β-catenin. In despite of varying IC50, galeterone at nanomolar concentrations significantly decreased viability, proliferation and migration of a panel of breast cancer cell lines regardless of clinical subtypes and genetic mutations, and to a higher extent than in normal breast cells. Galeterone significantly enhanced the effects of chemotherapeutic drugs in reducing proliferation and viability but not migration. The in vivo efficacy of galeterone as single drug alone and its ability in augmenting chemotherapy's efficacy were also shown in breast cancer xenograft mouse model. Mechanism analysis demonstrated that galeterone decreased MNK1/2 level and phosphorylation of eIF4E. In addition, galeterone decreased β-catenin level via promoting GSK-3β-mediated β-catenin degradation, and furthermore that Akt but not CK1 was involved in β-catenin degradation by galeterone. Rescue studies demonstrated that both MNK/eIF4E and β-catenin were responsible for anti-breast cancer activity of galeterone. Our study provides pre-clinical evidence to initialize clinical trials for breast cancer using galeterone in combination with chemotherapy. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CANCER chemotherapy
*EXOCRINE glands
*GENETIC mutation
*BREAST cancer
*COMBINATION drug therapy
*PROSTATE cancer
*RESEARCH
*HETEROCYCLIC compounds
*STEROIDS
*ANIMAL experimentation
*RESEARCH methodology
*ANTINEOPLASTIC agents
*CELL physiology
*CYTOSKELETAL proteins
*MEDICAL cooperation
*EVALUATION research
*CELLULAR signal transduction
*COMPARATIVE studies
*CELL lines
*BREAST tumors
*MICE
*PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 03445704
- Volume :
- 87
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Cancer Chemotherapy & Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 148041872
- Full Text :
- https://doi.org/10.1007/s00280-020-04195-w