Autophagy inhibition induced by EM-2 augments apoptosis via ROS-mediated ATM-Chk2-p53-p21 and MAPK pathway in lung and breast carcinoma
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PROVIDER: PRJNA1124931 | ENA |
REPOSITORIES: ENA
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Project description:Lung cancer (LC) and breast cancer (BC) are two common malignant tumors with the highest incidence rate in men and women worldwide, respectively. As the treatment effect of currently available therapies for LC and BC is unsatisfied, searching for new therapeutic drugs has become an urgent need to be addressed. EM-2, a natural sesquiterpene lactone isolated from Elephantopus mollis H.B.K., has been previously documented to exert anti-tumor effects on many cancers. However, the underlying molecular mechanisms have not been clearly elucidated. Thus, in the present study, we further investigated the anticancer effect of EM-2 on LC and BC with focusing on the involved molecular mechanisms. Our results suggest that EM-2 induces the impaired autophagy, which subsequently promotes ER stress-mediated apoptosis as well as ROS generation. ROS accumulation induced by EM-2 further simultaneously induces G2/M cell cycle arrest through ATM-Chk2-p53-p21 pathway and augments cell apoptosis via MAPK-mediated mitochondrial signaling pathway in LC and BC cells. These results may provide the experimental basis for future clinical application of EM-2 in the treatment for LC and BC.
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Project description:Extrachromosomal DNA (ecDNA) drives the evolution of cancer cells by conferring survival advantages over normal cells. However, the functional importance of ecDNA replication and maintenance is yet to be evaluated, and the molecular components that contribute to these processes remain largely unknown. Here, using CRISPR-C (circularization of genes and chromosomes by CRISPR) technology and synthetic circular DNA mimicking ecDNA identified in tumors, we generated ecDNA-positive (ecDNA+) cell models. Using these models, we identified the proteins involved in ecDNA replication and maintenance and found that DNA damage response (DDR)-related pathways were significantly enriched. We further demonstrated that ecDNA replication led to increased DDR and genome instability, and DDR was also essential for ecDNA maintenance. This is consistent with observations that ecDNA+ tumors exhibited higher DDR scores than ecDNA-negative (ecDNA–) tumors in patients. ATM, MDC1, and CHK2 were activated in ecDNA+ cells compared to ecDNA– cells. Moreover, ecDNA+ cells were more sensitive to ATM and CHK2 inhibition. We further found that topoisomerases and DNA ligase III (LIG3) are critical regulators for ecDNA replication, maintenance, and related DDR. In summary, our findings of the reciprocal interactions between ecDNA and DDR provide new insights into detection and therapy for ecDNA+ tumors.
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Project description:Homologous recombination-mediated DNA repair deficiency (HRD) predisposes to cancer development, but also provides therapeutic opportunities. Here, we identified an HRD gene signature that robustly predicted HRD status. Unexpectedly, concurrent loss of PTEN in BRCA1-deficient cells might extensively rewire the HR repair network and confer resistance to PARP inhibitor, partially through over-expression of TTK. We used the HRD gene signature as a drug discovery tool and found several PARP-inhibitor-synergizing agents through the connectivity map. Thus gene expression profiling can be used to define the functional status of the HR repair network providing prognostic and therapeutic information. Various shRNAs that target genes involved in homologous recombination (HR) were transfected in MCF-10A non-transformed breast cells lines. Stable HR gene knockdown MCF-10A cells were seeded 200000 at 10 cm plate. Cells were harvested after 48 hours culturing and used for gene expression profiling. The shRNAs that target ATM, ATR, CHK1, CHK2, and 53BP1 genes were transfected in MCF-10A non-transformed breast cell line by lentiviral particles and selected stable ATM, ATR, CHK1, CHK2, and 53BP1 knockdown MCF-10A cells. Scrambled control shRNA-transfected and wild type MCF-10A cells were applying as control. All knockdown and control MCF-10A cells were seeded with 2 x 10^5 cells at 10 cm culture plate. Cells were cultured in MCF-10A medium and harvested after 48 hours culturing. mRNA was extracted from collected cells and performing gene expression profiling. Three biological replicates were applied.
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