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Loss of EPS8 sensitizes non-small-cell lung carcinoma to chemotherapy-induced DNA damage
Yingqi Qiu1, Binyan Xu1, Jianhua Feng1
1Department of Hematology, Zhujiang Hospital, Southern Medical University, No. 253 Gongye Dadao Zhong, Guangzhou, Guangdong, 510285, P. R. China.
Abstract:
Epidermal growth factor receptor pathway substrate number 8 (EPS8) has been reported to be critical in mediating tumor progression. However, the molecular and biological consequences of EPS8 overexpression remain unclear. Here we evaluated whether EPS8 increased DNA damage repair in non-small-cell lung carcinoma (NSCLC) cells and the mechanism of EPS8-mediated DNA damage repair which influenced chemosensitivity. Serial studies of functional experiments revealed that EPS8 knockdown inhibited cell growth, induced cell-cycle arrest and increased cisplatin therapeutic effects on NSCLC. EPS8 was found to induce DNA damage repair via upregulation of phosphorylated-ATM and downregulation of the tumor suppressor p53 and G1 cell kinase inhibitor p21. Moreover, in conjunction with cisplatin, decreasing EPS8 protein levels further increased p53 protein level and inhibited ATM signaling. Transplanted tumor studies were also performed to demonstrate that EPS8 knockdown inhibited tumor growth and sensitized tumors to cisplatin treatment. In conclusion, we have described a novel molecular mechanism through which EPS8 is likely to be involved in cancer progression and chemoresistance via DNA damage repair, indicating that EPS8 expression may influence the response to chemotherapy. Therefore, targeting EPS8 may be a potential therapeutic approach for patients with NSCLC.
Insights
Epidermal growth factor receptor pathway substrate number 8 (EPS8) promotes non-small-cell lung cancer (NSCLC) progression and chemoresistance by enhancing DNA damage repair. Targeting EPS8 may improve chemotherapy effectiveness in NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Epidermal growth factor receptor pathway substrate number 8 (EPS8) is implicated in tumor progression.
- The precise role of EPS8 in non-small-cell lung carcinoma (NSCLC) and its impact on DNA damage repair and chemosensitivity are not fully understood.
Purpose of the Study:
- To investigate whether EPS8 overexpression enhances DNA damage repair in NSCLC cells.
- To elucidate the mechanism by which EPS8-mediated DNA damage repair influences chemosensitivity.
- To evaluate the therapeutic potential of targeting EPS8 in NSCLC.
Main Methods:
- Functional experiments including cell growth assays and cell-cycle analysis.
- Western blotting to assess protein levels of phosphorylated-ATM, p53, and p21.
- In vivo studies using transplanted tumor models in mice.
Main Results:
- Knockdown of EPS8 inhibited NSCLC cell growth, induced cell-cycle arrest, and enhanced cisplatin sensitivity.
- EPS8 promoted DNA damage repair by upregulating phosphorylated-ATM and downregulating p53 and p21.
- Reducing EPS8 levels in combination with cisplatin further increased p53 and inhibited ATM signaling, suppressing tumor growth in vivo.
Conclusions:
- EPS8 plays a significant role in NSCLC progression and chemoresistance through modulation of DNA damage repair pathways.
- Targeting EPS8 represents a potential therapeutic strategy to improve chemotherapy outcomes for NSCLC patients.
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