PKC-ζ mediated reduction of the extracellular vesicles-associated TGF-β1 overcomes radiotherapy resistance in breast cancer.

Autor: Zhang F; Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. fyzhang@ibp.ac.cn., Zheng Z; Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.; University of Chinese Academy of Sciences, Beijing, 100049, China., Wang L; School of Basic Medicine, Qingdao University, Qingdao, 266071, China., Zeng W; Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.; University of Chinese Academy of Sciences, Beijing, 100049, China., Wei W; Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.; University of Chinese Academy of Sciences, Beijing, 100049, China., Zhang C; Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China., Zhao Z; Thoracic Surgery Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. zhaoziran@cicams.ac.cn., Liang W; Protein and Peptide Pharmaceutical Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. weixx@ibp.ac.cn.; University of Chinese Academy of Sciences, Beijing, 100049, China. weixx@ibp.ac.cn.
Jazyk: angličtina
Zdroj: Breast cancer research : BCR [Breast Cancer Res] 2023 Apr 07; Vol. 25 (1), pp. 38. Date of Electronic Publication: 2023 Apr 07.
DOI: 10.1186/s13058-023-01641-4
Abstrakt: Background: Radiotherapy is widely applied in breast cancer treatment, while radiotherapy resistance is inevitable. TGF-β1 has been considered to be an endogenous factor for the development of radiotherapy resistance. As a large portion of TGF-β1 is secreted in an extracellular vesicles-associated form (TGF-β1 EV ), particularly in radiated tumors. Thus, the understanding of the regulation mechanisms and the immunosuppressive functions of TGF-β1 EV will pave a way for overcoming the radiotherapy resistance in cancer treatment.
Methods: The superoxide-Zinc-PKC-ζ-TGF-β1 EV pathway in breast cancer cells was identified through sequence alignments of different PKC isoforms, speculation and experimental confirmation. A series of functional and molecular studies were performed by quantitative real-time PCR, western blot and flow cytometry analysis. Mice survival and tumor growth were recorded. Student's t test or two-way ANOVA with correction was used for comparisons of groups.
Results: The radiotherapy resulted in an increased expression of the intratumoral TGF-β1 and an enhanced infiltration of the Tregs in the breast cancer tissues. The intratumoral TGF-β1 was found mainly in the extracellular vesicles associated form both in the murine breast cancer model and in the human lung cancer tissues. Furthermore, radiation induced more TGF-β1 EV secretion and higher percentage of Tregs by promoting the expression and phosphorylation of protein kinase C zeta (PKC-ζ). Importantly, we found that naringenin rather than 1D11 significantly improved radiotherapy efficacy with less side effects. Distinct from TGF-β1 neutralizing antibody 1D11, the mechanism of naringenin was to downregulate the radiation-activated superoxide-Zinc-PKC-ζ-TGF-β1 EV pathway.
Conclusions: The superoxide-zinc-PKC-ζ-TGF-β1 EV  release pathway was elucidated to induce the accumulation of Tregs, resulting in radiotherapy resistance in the TME. Therefore, targeting PKC-ζ to counteract TGF-β1 EV function could represent a novel strategy to overcome radiotherapy resistance in the treatment of breast cancer or other cancers.
Trial Registration: The using of patient tissues with malignant Non-Small Cell Lung Cancer (NSCLC) was approved by the ethics committees at Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (NCC2022C-702, from June 8th, 2022).
(© 2023. The Author(s).)
Databáze: MEDLINE
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