Dataset Information

ATF4 Gene Network Mediates Cellular Response to the Anticancer PAD Inhibitor YW3-56 in Triple-Negative Breast Cancer Cells.

ABSTRACT: We previously reported that a pan-PAD inhibitor, YW3-56, activates p53 target genes to inhibit cancer growth. However, the p53-independent anticancer activity and molecular mechanisms of YW3-56 remain largely elusive. Here, gene expression analyses found that ATF4 target genes involved in endoplasmic reticulum (ER) stress response were activated by YW3-56. Depletion of ATF4 greatly attenuated YW3-56-mediated activation of the mTORC1 regulatory genes SESN2 and DDIT4. Using the ChIP-exo method, high-resolution genomic binding sites of ATF4 and CEBPB responsive to YW3-56 treatment were generated. In human breast cancer cells, YW3-56-mediated cell death features mitochondria depletion and autophagy perturbation. Moreover, YW3-56 treatment effectively inhibits the growth of triple-negative breast cancer xenograft tumors in nude mice. Taken together, we unveiled the anticancer mechanisms and therapeutic potentials of the pan-PAD inhibitor YW3-56.

SUBMITTER: Wang S

PROVIDER: S-EPMC4394025 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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ATF4 Gene Network Mediates Cellular Response to the Anticancer PAD Inhibitor YW3-56 in Triple-Negative Breast Cancer Cells.

Wang Shu S Chen Xiangyun Amy XA Hu Jing J Jiang Jian-Kang JK Li Yunfei Y Chan-Salis Ka Yim KY Gu Ying Y Chen Gong G Thomas Craig C Pugh B Franklin BF Wang Yanming Y

Molecular cancer therapeutics 20150122 4

We previously reported that a pan-PAD inhibitor, YW3-56, activates p53 target genes to inhibit cancer growth. However, the p53-independent anticancer activity and molecular mechanisms of YW3-56 remain largely elusive. Here, gene expression analyses found that ATF4 target genes involved in endoplasmic reticulum (ER) stress response were activated by YW3-56. Depletion of ATF4 greatly attenuated YW3-56-mediated activation of the mTORC1 regulatory genes SESN2 and DDIT4. Using the ChIP-exo method, hi ...[more]

PMID: 25612620

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Project description:RAPTA-EA1 is a promising glutathione transferase (GSTP-1) inhibitor that has previously been shown to inhibit the growth of various breast cancer cells. We studied the anticancer activity of RAPTA-EA1 on triple-negative BRCA1 competent breast cancer MDA-MB-231 cells. MDA-MB-231 cells are significantly more sensitive to RAPTA-EA1 than MCF-7 cells. Treatment reveals a higher degree of cytotoxicity than cisplatin against both cell lines. Ruthenium accumulation in MDA-MB-231 cells is mainly in the nuclear fraction (43%), followed by the cytoplasm (30%), and the mitochondria (27%). RAPTA-EA1 blocks cell growth at the G2/M phase, leading to nuclear condensation and cell death. The compound slightly inhibits DNA replication of the 3,426-bp fragment of the BRCA1 exon 11 of the cells, with approximately 0.6 lesion per the BRCA1 fragment. The expression of BRCA1 mRNA and its protein in the Ru-treated cells is curtailed by 50-80% compared to the untreated controls. Growth inhibition of the triple-negative BRCA1 wild-type MDA-MB-231 and the sporadic BRCA1 wild-type MCF-7 cells by olaparib (a poly [ADP-ribose] polymerase (PARP) inhibitor) is dose-dependent, with MDA-MB-231 cells being two-fold less susceptible to the drug than MCF-7 cells. Combining olaparib with RAPTA-EA1 results in a combination index (CI) of 0.78 (almost additive) in MDA-MB-231 cells and 0.24 (potent synergy) in the MCF-7 cells. The PARP inhibitor alone differently regulates the expression of BRCA1 mRNA in both cell lines, whereas the olaparib-RAPTA-EA1 combination induces overexpression of BRCA1 mRNA in these cells. However, the expression level of the BRCA1 protein is dramatically reduced after treatment with the combined inhibitors, compared with the untreated controls. This observation highlights the cellular responses of triple-negative BRCA1 proficient breast cancer MDA-MB-231 cells to RAPTA-EA1 through BRCA1 inhibition and provides insights into alternative treatments for breast cancer.

Dataset Information

ATF4 Gene Network Mediates Cellular Response to the Anticancer PAD Inhibitor YW3-56 in Triple-Negative Breast Cancer Cells.

Publications

ATF4 Gene Network Mediates Cellular Response to the Anticancer PAD Inhibitor YW3-56 in Triple-Negative Breast Cancer Cells.

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