Farnesol-Induced Apoptosis in Human Lung Carcinoma Cells Is Coupled to the Endoplasmic Reticulum Stress Response

Joo, Joung Hyuck; Liao, Grace; Collins, Jennifer B.; Grissom, Sherry F.; Jetten, Anton M.

doi:10.1158/0008-5472.can-07-0931

Cited by 118 publications

(121 citation statements)

References 49 publications

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“…S5). Because other proapoptotic genes detected in our study are also often activated during ESR (39), the data suggest that STAT3 ND suppression may be especially important for STAT3 functions under conditions of ESR in cancer cells. The identification of differences in epigenetic mechanisms that underlie differential activity of the STAT3 ND in normal and cancer cells can offer novel potential therapeutic targets for cancer treatment.…”

Section: St3-h2a2mentioning

confidence: 58%

STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain

Timofeeva¹,

Tarasova

Zhang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

126

124

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Activation of STAT3 in cancers leads to gene expression promoting cell proliferation and resistance to apoptosis, as well as tumor angiogenesis, invasion, and migration. In the characterization of effects of ST3-H2A2, a selective inhibitor of the STAT3 N-terminal domain (ND), we observed that the compound induced apoptotic death in cancer cells associated with robust activation of proapoptotic genes. Using ChIP and tiling human promoter arrays, we found that activation of gene expression in response to ST3-H2A2 is accompanied by altered STAT3 chromatin binding. Using inhibitors of STAT3 phosphorylation and a dominant-negative STAT3 mutant, we found that the unphosphorylated form of STAT3 binds to regulatory regions of proapoptotic genes and prevents their expression in tumor cells but not normal cells. siRNA knockdown confirmed the effects of ST3-HA2A on gene expression and chromatin binding to be STAT3 dependent. The STAT3-binding region of the C/EBP-homologous protein (CHOP) promoter was found to be localized in DNaseI hypersensitive site of chromatin in cancer cells but not in nontransformed cells, suggesting that STAT3 binding and suppressive action can be chromatin structure dependent. These data demonstrate a suppressive role for the STAT3 ND in the regulation of proapoptotic gene expression in cancer cells, providing further support for targeting STAT3 ND for cancer therapy.H3K9me3 | peptide inhibitor | prostate cancer | transcription factor S TAT3, a member of the STAT family, is a key signaling protein that transduces extracellular signals to the nucleus and regulates transcription of genes (1). Following ligand stimulation, STAT3 is phosphorylated on Y705 tyrosine residue, dimerizes, and translocates to the nucleus to bind its cognate DNA-response elements, activating gene transcription (1). Constitutively activated STAT3 mediates deregulated growth, survival, and angiogenesis (2, 3). STAT3 is widely recognized as a potential drug target for cancer therapy, and various approaches, including targeting of upstream tyrosine kinases and direct inhibitors of STAT3 dimerization, have been advanced to inhibit STAT3 signaling in cancers (4). However, unphosphorylated STAT3 (U-STAT3) has also been shown to influence gene transcription, both in response to cytokines and in cancer cells, albeit by mechanisms that are distinct from those activated by phosphorylated STAT3 (5). We have developed a highly selective inhibitor of STAT3 ND, ST3-Hel2A-2 (ST3-H2A2), that binds to the N-terminal domain (ND) and inhibits STAT3 signaling (6). STAT3 ND is involved in the interactions of two STAT dimers on neighboring sites to form a more stable tetramer and the interactions with histone-modifier proteins to induce changes in chromatin structure (reviewed in ref. 7). These complex interactions may greatly affect STAT3-dependent transcriptional activity, suggesting that the STAT3 ND mediates important regulatory functions of STAT3 in normal cells (8) and in cancer (9). ST3-H2A2 induces death in breast cancer cells MDA-MB-231 an...

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Section: St3-h2a2mentioning

confidence: 58%

STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain

Timofeeva¹,

Tarasova

Zhang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

126

124

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“…A significant fraction of the mRNA species (33%) identified in the initial A549 screen were modulated in the same manner by the combination of pazopanib and lapatinib (but not by other chemotherapeutic agents such as cisplatin, or drug combinations; data not shown) in all the cell lines (Figure 5c; Supplementary Table S3), suggesting that pazopanib and lapatinib might exert synergistic effects on multiple different malignancies. Among the 58 genes that were induced specifically by the combination regimen in all cell lines, several have previously been involved in apoptotic signaling, in particular p53 (Pietsch et al, 2008), PHLDA1 (also known as T-cell-death-associated gene 51, TDAG51) (Hayashida et al, 2006;Joo et al, 2007;Oberst et al, 2008) and RHOT1 (ras homolog gene family, member T1; also known as mitochondrial Rho; Miro1) (Fransson et al, 2003). Indeed, we observed that the combination of pazopanib and lapatinib was able to kill the five carcinoma cell lines included in the transcriptome analysis, as well as ovarian (SKOV3) and cervix cancer cells (HeLa), yielding highly significant synergistic effects of both compounds as compared to each of them alone (Figure 5d; Supplementary Table S4).…”

Section: Resultsmentioning

confidence: 99%

Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines

et al. 2009

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Pazopanib and lapatinib are two tyrosine kinase inhibitors that have been designed to inhibit the VEGF tyrosine kinase receptors 1, 2 and 3 (pazopanib), and the HER1 and HER2 receptors in a dual manner (lapatinib). Pazopanib has also been reported to mediate inhibitory effect on a selected panel of additional tyrosine kinases such as PDGFR and c-kit. Here, we report that pazopanib and lapatinib act synergistically to induce apoptosis of A549 non-small-cell lung cancer cells. Systematic assessment of the kinome revealed that both pazopanib and lapatinib inhibited dozens of different tyrosine kinases and that their combination could suppress the activity of some tyrosine kinases (such as c-Met) that were not or only partially affected by either of the two agents alone. We also found that pazopanib and lapatinib induced selective changes in the transcriptome of A549 cells, some of which were specific for the combination of both agents. Analysis of a panel of unrelated human carcinoma cell lines revealed a signature of 52 genes whose up-or downregulation reflected the combined action of pazopanib and lapatinib. Indeed, pazopanib and lapatinib exerted synergistic cytotoxic effects on several distinct non-smallcell lung cancer cells as well as on unrelated carcinomas. Altogether, these results support the contention that combinations of tyrosine kinase inhibitors should be evaluated for synergistic antitumor effects. Such combinations may lead to a 'collapse' of pro-survival signal transduction pathways that leads to apoptotic cell death.

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“…[31][32][33] To date activation of one or more branches of the UPR has been reported in oesophageal adenocarcinomas, 34 breast, [35][36][37] gastric 38 and lung cancers. 39 Tumour cells have an important interaction with the cellular context in which they are Targeting the UPR in cancer found including dependence on fundamental limiting factors such as hypoxia, 40 lack of nutrients and acidosis. These factors can be partially overcome if the tumour is able to establish a blood supply via secretion of pro-angiogenic factors.…”

mentioning

confidence: 99%

Untangling the unfolded protein response

Davenport¹,

Morgan²,

Davies³

2008

Cell Cycle

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Farnesol-Induced Apoptosis in Human Lung Carcinoma Cells Is Coupled to the Endoplasmic Reticulum Stress Response

Cited by 118 publications

References 49 publications

STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain

STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain

Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines

Untangling the unfolded protein response

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