Author:
Wang Ming,Pan Zhenzhen,Chu Xu,Yao Xiaohan,Duan Xixi,Wan Jiajia,Lou Xiaohan,Li Wenqing,Yan Yan,Chen Lin,An Junfeng,Qin Zhihai
Abstract
Abstract
Background
PTEN loss has been identified in various tumor types and is linked to unfavorable clinical outcomes. In addition to PTEN mutation, multiple mechanisms contribute to PTEN loss during tumor development. However, the natural selection process of PTEN-deficient tumor cells remains unclear. Here, we aimed at further elucidating the role of PTEN-L in tumor progression.
Methods
PTEN knockout cell lines were generated using CRISPR/Cas9 technology. Ni-NTA affinity column chromatography was employed for PTEN-L purification. Tumor cell metastasis was evaluated in murine models and observed using the IVIS Spectrum Imaging System. RNA-sequencing, western blotting, PCR, flow cytometry, and cell proliferation assays were employed to investigate tumor cell dormancy and related mechanisms.
Results
The chemotherapeutic drugs, cisplatin, paclitaxel, and doxorubicin, induced tumor cells to secrete PTEN-long (PTEN-L), which shields PTEN-deficient tumor cells from chemotherapy-induced apoptosis better than it shields PTEN-intact cells. Further investigation revealed that PTEN-L treatment induced dormancy in PTEN-null tumor cells, characterized by an increase in p16 and p27 levels, cell-cycle arrest, reduced cell proliferation, and enhanced DNA repair. Furthermore, PTEN-L treatment selectively promoted the accumulation and growth of PTEN-null tumor cells in the lungs of C57BL/6J mice, while evading immune surveillance. Mechanistically, PTEN-L induced dormancy in PTEN-null tumor cells by activating the p38 signaling pathway. Addition of a p38 inhibitor effectively reversed dormancy and growth of PTEN-deficient tumor cells in the lungs. We also demonstrated that PTEN expression played a pivotal role in determining the outcome of PTEN-L-mediated antitumor therapy.
Conclusions
In summary, PTEN-L was identified as a potent inducer of dormancy in PTEN-deficient tumor cells, which increased their efficient selection within the tumor microenvironment.
Funder
National Natural Science Foundation of China
Henan Provincial Science and Technology Research Project
Publisher
Springer Science and Business Media LLC
Reference37 articles.
1. Milella M, Falcone I, Conciatori F, et al. PTEN: multiple functions in human malignant tumors. [J] Front Oncol. 2015;5:24.
2. Zhang HY, Liang F, Jia ZL, et al. PTEN mutation, methylation and expression in breast cancer patients [J]. Oncol Lett. 2013;6(1):161–8.
3. Correia NC, Gírio A, Antunes I, et al. The multiple layers of non-genetic regulation of PTEN tumour suppressor activity [J]. Eur J cancer (Oxford England: 1990). 2014;50(1):216–25.
4. Hopkins BD, Fine B, Steinbach N, et al. A secreted PTEN phosphatase that enters cells to alter signaling and survival [. J] Sci. 2013;341(6144):399–402.
5. Tan L, Xu Z, Mao Q, et al. Purified PTEN-Long induces Liver Cancer cells to Undergo Autophagy and apoptosis [J]. Front Surg. 2022;9:767611.