The Role of STAT3 in Non-Small Cell Lung Cancer

Harada, Daijiro; Takigawa, Nagio; Kiura, Katsuyuki

doi:10.3390/cancers6020708

Cited by 167 publications

(155 citation statements)

References 98 publications

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“…By contrast, silenceing STAT3 demonstrated more sensitive to the cytotoxic agents. Also, STAT3 plays a crucial role in chemotherapy [40]. The findings of a previous study suggested that DM at the time of diagnosis had no association with survival in patients with SCLC [41], although small cell lung cancer (SCLC) patients generally only survive for a short time anyway, and hence survival may not be affected by the presence of DM.…”

Section: Discussionmentioning

confidence: 87%

Prognostic Significance of Diabetes Mellitus in Locally Advanced Non-small Cell Lung Cancer

Imai¹

2017

kmj

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Section: Discussionmentioning

confidence: 87%

Prognostic Significance of Diabetes Mellitus in Locally Advanced Non-small Cell Lung Cancer

Imai¹

2017

kmj

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“…Signal transducer and activator of transcription 3 (Stat3) signaling is constitutively activated and associated with chemoresistance in NSCLC [10]. Inhibition of Stat3 signaling has been documented to sensitize A549 NSCLC cells to DNA damaging drugs doxorubicin and CDDP [11].…”

Section: Introductionmentioning

confidence: 99%

Periostin Contributes to Cisplatin Resistance in Human Non-Small Cell Lung Cancer A549 Cells via Activation of Stat3 and Akt and Upregulation of Survivin

Jin

Liu

2016

Cell Physiol Biochem

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Background/Aims: Periostin is upregulated in non-small cell lung cancer (NSCLC). This study was done to explore the function of periostin in the development of cisplatin (CDDP) resistance in NSCLC. Methods: The effects of overexpression or knockdown of periostin on CDDP sensitivity was examined in A549 cells. The involvement of signal transducer and activator of transcription 3 (Stat3) and Akt signaling in the action of periostin was checked. The in vivo effect of periostin silencing on CDDP susceptibility was determined in a mouse xenograft model. Results: Periostin was significantly upregulated in CDDP-resistant A549 cells, compared to parental controls. Overexpression of periostin rendered A549 cells more resistant to CDDP-induced apoptosis and enhanced Stat3 and Akt phosphorylation and survivin expression. Periostin-mediated protection against CDDP-induced apoptosis was compromised by downregulation of survivin. Furthermore, knockdown of periostin re-sensitized CDDP-resistant A549 cells to CDDP. After CDDP treatment, greater volume reduction was observed in periostin-silenced xenograft tumors than in control tumors, which was accompanied by reduced levels of phosphorylated Stat3 and survivin in periostin-depleted tumors. Conclusion: In conclusion, periostin promotes CDDP resistance in NSCLC cells largely through activation of Stat3 and Akt and upregulation of survivin and thus represents a promising target for overcoming CDDP resistance.

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“…Thus, targeting Stat3 has potential for prevention and treatment of cancers [17, 19]. Stat3 is persistently activated in NSCLC [14, 20], overexpression of Stat3 resulted in poor prognosis, thus, high activation of p-Stat3 was considered as a diagnostic marker in patients with NSCLC [16]. However, the potential role of this molecule in mediating the effect of ATL-1 has not been recognized.…”

Section: Introductionmentioning

confidence: 99%

“…Deregulation of Stat3 promoted tumor growth through regulating the expression of genes involved in proliferation, apoptosis, and angiogenesis, among others [14, 15]. Several reports showed that inhibition of Stat3 suppressed the growth of cancer cells and enhanced the sensitivity to anticancer agents in several cancer types [16-18]. Thus, targeting Stat3 has potential for prevention and treatment of cancers [17, 19].…”

Section: Introductionmentioning

confidence: 99%

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

Xiao¹,

Zheng²,

Wu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Atractylodes macrocephula Koidz is an important ingredient in traditional Chinese herbs. One major bioactive compound, atractylenolide-1 (ATL-1), was reported to have anti-inflammatory and anti-tumor activities. However, the underlying molecular mechanism associated to this has not been well elucidated. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Western blot analysis was performed to examine the phosphorylation and protein expression of extracellular signaling-regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription 3 (Stat3), 3-phosphoinositide dependent protein kinase-1 (PDK1) and transcription factor SP1. QRT-PCR was used to examine the mRNA levels of PDK1 gene. Exogenously expressions of Stat3, PDK1 and SP1 were carried out by transient transfection assays. PDK1 promoter activity was measured by Secrete-Pair Dual Luminescence Assay Kit. A nude mice xenograft model was used to confirm the findings in vitro. Results: We showed that ATL-1 inhibited human lung cancer cell growth and induced cell cycle arrest. Furthermore, we found that ATL-1 stimulated phosphorylation of ERK1/2, inhibited phosphorylation and protein expressions of Stat3 and SP1; the latter were abrogated in the presence of MEK/ERK inhibitor PD98059. Moreover, ATL-1 reduced the protein, mRNA expression and promoter activity of PDK1. Intriguingly, exogenously expressed Stat3 and SP1 overcame ATL-1-inhibited SP1 and Stat3, and PDK1 protein expressions, respectively. Moreover, overexpression of PDK1 resisted the ATL-1-inhibited lung cancer cell growth. In consistent with the results in vitro, ATL-1 inhibited tumor growth, protein expressions of Stat3, SP1 and PDK1, and induced phosphorylation of ERK1/2 in vivo. Conclusion: In summary, our results show that ATL-1 inhibits lung cancer cell growth through activation of ERK1/2, followed by suppressing SP1 protein expression. ATL-1 also reduces phosphorylation and protein levels of Stat3. These are mutual regulation between Stat3 and SP1 proteins affected by ATL-1. This ultimately suppresses PDK1 gene expression. This study reveals a novel mechanism by which ATL-1 inhibits growth of lung cancer cells. Thus, targeting PDK1 pinpoints a potential in the lung cancer treatment.

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The Role of STAT3 in Non-Small Cell Lung Cancer

Cited by 167 publications

References 98 publications

Prognostic Significance of Diabetes Mellitus in Locally Advanced Non-small Cell Lung Cancer

Prognostic Significance of Diabetes Mellitus in Locally Advanced Non-small Cell Lung Cancer

Periostin Contributes to Cisplatin Resistance in Human Non-Small Cell Lung Cancer A549 Cells via Activation of Stat3 and Akt and Upregulation of Survivin

Activation of ERK and Mutual Regulation of Stat3 and SP1 Contribute to Inhibition of PDK1 Expression by Atractylenolide-1 in Human Lung Cancer Cells

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