XZH-5 Inhibits STAT3 Phosphorylation and Enhances the Cytotoxicity of Chemotherapeutic Drugs in Human Breast and Pancreatic Cancer Cells

Liu, Aiguo; Liu, Yan; Jin, Zhigang; Hu, Qun; Lin, Lili; Jou, David; Yang, Jing; Xu, Zhenghu; Wang, Hong; Li, Chenglong; Lin, Jiayuh

doi:10.1371/journal.pone.0046624

Cited by 27 publications

(20 citation statements)

References 27 publications

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“…To examine whether Stat3 was functionally active in S16 cells, we examined the expression of the STAT3 upregulated targets, MMP7 31 , Bcl-2 32 and downregulated target, Mac-2bp 33 in S16 and C9 cells. Upregulation of MMP7 and Bcl-2 while down-regulation of Mac-2BP mRNA was observed in S16 cells as compared to C9 cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic silencing of the NR4A3 tumor suppressor, by aberrant JAK/STAT signaling, predicts prognosis in gastric cancer

Yeh

Chang

Lin

et al. 2016

Sci Rep

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While aberrant JAK/STAT signaling is crucial to the development of gastric cancer (GC), its effects on epigenetic alterations of its transcriptional targets remains unclear. In this study, by expression microarrays coupled with bioinformatic analyses, we identified a putative STAT3 target gene, NR4A3 that was downregulated in MKN28 GC daughter cells overexpressing a constitutively activated STAT3 mutant (S16), as compared to an empty vector control (C9). Bisulphite pyrosequencing and demethylation treatment showed that NR4A3 was epigenetically silenced by promoter DNA methylation in S16 and other GC cell lines including AGS cells, showing constitutive activation of STAT3. Subsequent experiments revealed that NR4A3 promoter binding by STAT3 might repress its transcription. Long-term depletion of STAT3 derepressed NR4A3 expression, by promoter demethylation, in AGS GC cells. NR4A3 re-expression in GC cell lines sensitized the cells to cisplatin, and inhibited tumor growth in vitro and in vivo, in an animal model. Clinically, GC patients with high NR4A3 methylation, or lower NR4A3 protein expression, had significantly shorter overall survival. Intriguingly, STAT3 activation significantly associated only with NR4A3 methylation in low-stage patient samples. Taken together, aberrant JAK/STAT3 signaling epigenetically silences a potential tumor suppressor, NR4A3, in gastric cancer, plausibly representing a reliable biomarker for gastric cancer prognosis.

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Section: Resultsmentioning

confidence: 99%

Epigenetic silencing of the NR4A3 tumor suppressor, by aberrant JAK/STAT signaling, predicts prognosis in gastric cancer

Yeh

Chang

Lin

et al. 2016

Sci Rep

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“…A lot of novel small molecular inhibitors of STAT3 have been reported to suppress cancer cells and tumor growth, such as LLL12 [22], LY5 [23], XZH-5 [24] and so on. However, to date, the translation of anti-STAT3 therapies into clinical trials has been difficult [25–26].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, as an approved drug by FDA, the security and permeability of Raloxifene are superior as compared to other reported novel molecular inhibitors of IL-6/GP130/STAT3, such as MDL-A [15], LLL12 [23], LY5 [24], and XZH-5 [25]. Therefore, Raloxifene is more likely to apply to clinical trails.…”

Section: Discussionmentioning

confidence: 99%

Growth-suppressive activity of raloxifene on liver cancer cells by targeting IL-6/GP130 signaling

Wang

Zhao

et al. 2017

Oncotarget

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BackgroundInterleukin-6 (IL-6) is a multifunctional cytokine, which is involved in the regulation of differentiation and growth of certain types of tumor cells. Constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) induced by IL-6 is frequently detected in liver cancer and has emerged as a viable molecular target for liver cancer treatment. However, few inhibitors targeting up-streams of STAT3 are available for the therapy of liver cancer. We reported the discovery of EVISTA (Raloxifene HCl) as novel inhibitor of IL-6/GP130 protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning. The possible effect of Raloxifene in STAT3 signaling or liver cancer cells is still unclear.ResultsRaloxifene inhibited the P-STAT3 stimulated by IL-6, but not the induction of STAT1 and STAT6 phosphorylation by IFN-γ, IFN-α, and IL-4. Raloxifene inhibited STAT3 phosphorylation and resulted in the induction apoptosis on human liver cancer cell-lines. Raloxifene inhibited the targets of STAT3, such as Bcl-2, Bcl-xl and survivin and cell viability, cell migration, and colony formation in liver cancer cells. Further, daily administration of Raloxifene suppressed the Hep-G2 tumor growth in mice in vivo.Materials and MethodsThe inhibitory effect on STAT3 phosphorylation and activity as well as cell viability, migration, and colony forming ability by Raloxifene was examined in human liver cancer cells. Tumor growth was detected via mouse xenograft tumor mode.ConclusionsOur results suggest that Raloxifene is a potent IL-6/GP130 inhibitor and may be a chemoprevention agent for liver cancer by targeting persistent STAT3 signaling.

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“…Moreover, inhibition of STAT3 with various pharmacological agents including small molecular inhibitors suppresses tumor growth, recurrence and invasion in breast cancer cell lines as well as in a human-xenograft model (Liu et al, 2012; Zhang et al, 2012). A more detailed analysis of the effect of STAT3 on breast tumors is also presented elsewhere in this issue.…”

Section: Stats In Tumorigenesismentioning

confidence: 99%

STAT signaling in mammary gland differentiation, cell survival and tumorigenesis

Haricharan

2014

Molecular and Cellular Endocrinology

101

111

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The mammary gland is a unique organ that undergoes extensive and profound changes during puberty, menstruation, pregnancy, lactation and involution. The changes that take place during puberty involve large-scale proliferation and invasion of the fat-pad. During pregnancy and lactation, the mammary cells are exposed to signaling pathways that inhibit apoptosis, induce proliferation and invoke terminal differentiation. Finally, during involution the mammary gland is exposed to milk stasis, programed cell death and stromal reorganization to clear the differentiated milk-producing cells. Not surprisingly, the signaling pathways responsible for bringing about these changes in breast cells are often subverted during the process of tumorigenesis. The STAT family of proteins is involved in every stage of mammary gland development, and is also frequently implicated in breast tumorigenesis. While the roles of STAT3 and STAT5 during mammary gland development and tumorigenesis are well studied, others members, e.g. STAT1 and STAT6, have only recently been observed to play a role in mammary gland biology. Continued investigation into the STAT protein network in the mammary gland will likely yield new biomarkers and risk factors for breast cancer, and may also lead to novel prophylactic or therapeutic strategies against breast cancer.

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XZH-5 Inhibits STAT3 Phosphorylation and Enhances the Cytotoxicity of Chemotherapeutic Drugs in Human Breast and Pancreatic Cancer Cells

Cited by 27 publications

References 27 publications

Epigenetic silencing of the NR4A3 tumor suppressor, by aberrant JAK/STAT signaling, predicts prognosis in gastric cancer

Epigenetic silencing of the NR4A3 tumor suppressor, by aberrant JAK/STAT signaling, predicts prognosis in gastric cancer

Growth-suppressive activity of raloxifene on liver cancer cells by targeting IL-6/GP130 signaling

STAT signaling in mammary gland differentiation, cell survival and tumorigenesis

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