PKC-ζ mediated reduction of the extracellular vesicles-associated TGF-ß1 overcomes radiotherapy resistance in breast cancer.
Breast Cancer Res
; 25(1): 38, 2023 04 07.
Article
em En
| MEDLINE
| ID: mdl-37029374
ABSTRACT
BACKGROUND:
Radiotherapy is widely applied in breast cancer treatment, while radiotherapy resistance is inevitable. TGF-ß1 has been considered to be an endogenous factor for the development of radiotherapy resistance. As a large portion of TGF-ß1 is secreted in an extracellular vesicles-associated form (TGF-ß1EV), particularly in radiated tumors. Thus, the understanding of the regulation mechanisms and the immunosuppressive functions of TGF-ß1EV will pave a way for overcoming the radiotherapy resistance in cancer treatment.METHODS:
The superoxide-Zinc-PKC-ζ-TGF-ß1EV 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-ß1 and an enhanced infiltration of the Tregs in the breast cancer tissues. The intratumoral TGF-ß1 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-ß1EV 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-ß1 neutralizing antibody 1D11, the mechanism of naringenin was to downregulate the radiation-activated superoxide-Zinc-PKC-ζ-TGF-ß1EV pathway.CONCLUSIONS:
The superoxide-zinc-PKC-ζ-TGF-ß1EV release pathway was elucidated to induce the accumulation of Tregs, resulting in radiotherapy resistance in the TME. Therefore, targeting PKC-ζ to counteract TGF-ß1EV 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).Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Quinase C
/
Neoplasias da Mama
/
Carcinoma Pulmonar de Células não Pequenas
/
Fator de Crescimento Transformador beta1
/
Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Breast Cancer Res
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China