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DNA Damage-Response Pathway Heterogeneity of Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to
Sheng-Yong Yang1, Yi Li2, Guo-Shun An3
1Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. yangshengyong@cqmu.edu.cn.
Abstract:
Human lung cancer H1299 (p53-null) cells often display enhanced susceptibility to chemotherapeutics comparing to A549 (p53-wt) cells. However, little is known regarding to the association of DNA damage-response (DDR) pathway heterogeneity with drug sensitivity in these two cells. We investigated the DDR pathway differences between A549 and H1299 cells exposed to 8-chloro-adenosine (8-Cl-Ado), a potential anticancer drug that can induce DNA double-strand breaks (DSBs), and found that the hypersensitivity of H1299 cells to 8-Cl-Ado is associated with its DSB overaccumulation. The major causes of excessive DSBs in H1299 cells are as follows: First, defect of p53-p21 signal and phosphorylation of SMC1 increase S phase cells, where replication of DNA containing single-strand DNA break (SSB) produces more DSBs in H1299 cells. Second, p53 defect and no available induction of DNA repair protein p53R2 impair DNA repair activity in H1299 cells more severely than A549 cells. Third, cleavage of PARP-1 inhibits topoisomerase I and/or topoisomerase I-like activity of PARP-1, aggravates DNA DSBs and DNA repair mechanism impairment in H1299 cells. Together, DDR pathway heterogeneity of cancer cells is linked to cancer susceptibility to DNA damage-based chemotherapeutics, which may provide aid in design of chemotherapy strategy to improve treatment outcomes.
Insights
p53-null lung cancer cells (H1299) show higher sensitivity to 8-chloro-adenosine (8-Cl-Ado) due to DNA double-strand break (DSB) overaccumulation. This is linked to defective DNA repair pathways and p53-p21 signaling.
Area of Science:
- Cancer Biology
- Molecular Oncology
- DNA Damage Response
Background:
- Human lung cancer H1299 (p53-null) cells exhibit greater sensitivity to chemotherapeutics than A549 (p53-wild-type) cells.
- The relationship between DNA damage-response (DDR) pathway variations and drug sensitivity in these cell lines is not well understood.
Purpose of the Study:
- To investigate the differences in DDR pathways between A549 and H1299 cells when exposed to 8-chloro-adenosine (8-Cl-Ado).
- To understand the mechanisms behind the hypersensitivity of H1299 cells to 8-Cl-Ado, a drug inducing DNA double-strand breaks (DSBs).
Main Methods:
- Comparative analysis of DDR pathways in A549 and H1299 cells treated with 8-Cl-Ado.
- Assessment of DSB accumulation, cell cycle progression, and DNA repair protein activity.
Main Results:
- H1299 cells demonstrated hypersensitivity to 8-Cl-Ado, associated with significant DSB overaccumulation.
- Defects in the p53-p21 pathway and increased S phase cells contributed to DSB formation in H1299 cells.
- Impaired DNA repair in H1299 cells was linked to p53 deficiency, lack of p53R2 induction, and PARP-1 cleavage, which also inhibited topoisomerase activity.
Conclusions:
- Heterogeneity in DDR pathways influences cancer cell susceptibility to DNA damage-based chemotherapeutics like 8-Cl-Ado.
- Understanding these DDR differences can inform the design of improved chemotherapy strategies for lung cancer.
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