Targeting STAT3 inhibition to reverse cisplatin resistance

Sun, Chen; Nie, Jianhui; Huang, Jie-Peng; Zheng, Guangjuan; Feng, Bing

doi:10.1016/j.biopha.2019.109135

Cited by 60 publications

(45 citation statements)

References 123 publications

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“…In cervical cancer, clinical trials are required to find out whether the use of these molecules can have a positive effect on the overall and disease-free survival of patients, in addition to evaluating the toxicity of these treatments, as the reports indicate that STAT3 inhibitors are highly toxic. Experimental data in cervical tumor cells show that JAK2, STAT3, and STAT5 inhibitors reduce cell proliferation, induce apoptosis, and improve response to other drugs such as cisplatin [ 99 , 163 , 164 , 165 , 166 ]. Strategies to inhibit or reduce STAT3 activation include the use of interfering STAT3 siRNAs, which reduce the resistance of cervical tumor cells to cisplatin treatment.…”

Section: Inhibition Of the Jak/stat Pathway As A Therapeutic Targementioning

confidence: 99%

“…Strategies to inhibit or reduce STAT3 activation include the use of interfering STAT3 siRNAs, which reduce the resistance of cervical tumor cells to cisplatin treatment. Additionally, the use of some compounds such as propofol, arctigenin, and mahanin improves the induction of cell death by inhibiting STAT3 [ 163 , 164 , 165 , 166 , 167 , 168 ]. The JAK/STAT pathway participates in immune activation and regulation processes, including those involved in tumor cell recognition and tumor-driven immune escape.…”

Section: Inhibition Of the Jak/stat Pathway As A Therapeutic Targementioning

confidence: 99%

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Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

Gutiérrez‐Hoya

Soto‐Cruz²

2020

Cells

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The janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is associated with the regulation of essential cellular mechanisms, such as proliferation, invasion, survival, inflammation, and immunity. Aberrant JAK/STAT signaling contributes to cancer progression and metastatic development. STAT proteins play an essential role in the development of cervical cancer, and the inhibition of the JAK/STAT pathway may be essential for enhancing tumor cell death. Persistent activation of different STATs is present in a variety of cancers, including cervical cancer, and their overactivation may be associated with a poor prognosis and poor overall survival. The oncoproteins E6 and E7 play a critical role in the progression of cervical cancer and may mediate the activation of the JAK/STAT pathway. Inhibition of STAT proteins appears to show promise for establishing new targets in cancer treatment. The present review summarizes the knowledge about the participation of the different components of the JAK/STAT pathway and the participation of the human papillomavirus (HPV) associated with the process of cellular malignancy.

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Section: Inhibition Of the Jak/stat Pathway As A Therapeutic Targementioning

confidence: 99%

Section: Inhibition Of the Jak/stat Pathway As A Therapeutic Targementioning

confidence: 99%

Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

Gutiérrez‐Hoya

Soto‐Cruz²

2020

Cells

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“…Indeed, high expression of activated STAT3 has been shown to contribute to cisplatin resistance in ovarian cancer [33]. Moreover, abrogation of STAT3 activity has been shown to circumvent cisplatin resistance in ovarian cancer cells [34], making it a promising target to reverse cisplatin resistance in ovarian and other cancer types [33][34][35]. It is therefore likely that the early activation of STAT3 we observed in response to cisplatin, in CD44-expressing cells, and mainly in CD44v6-expressing cells, is contributing to increase apoptosis resistance to this drug in the isogenic MKN74 cell line model.…”

Section: Discussionmentioning

confidence: 99%

Expression of CD44v6-Containing Isoforms Influences Cisplatin Response in Gastric Cancer Cells

Pereira

Ferreira

Mendes

et al. 2020

Cancers

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CD44v6-containing isoforms are frequently de novo expressed in gastric cancer (GC). Whether CD44v6 has a central role in GC transformation and/or progression, whether it conditions response to therapy or whether it is only a bystander marker is still not known. Therefore, we aimed to clarify the role of CD44v6 in GC. We generated GC isogenic cell lines stably expressing CD44s or CD44v6 and tested them for different cancer hallmarks and response to cisplatin, and we further confirmed our findings in cells that endogenously express CD44v6. No correlation between overexpression of CD44v6 and the tested cancer hallmarks was observed, suggesting CD44v6 is not a driver of GC progression. Upon cisplatin treatment, CD44v6+ cells survive better and have lower apoptosis levels than CD44v6− cells, possibly due to concomitant activation of STAT3 and P38. In co-culture experiments, we discovered that CD44v6+ cells are involved in GC cell overgrowth after cisplatin treatment. In conclusion, we show that CD44v6 expression increases cell survival in response to cisplatin treatment in GC cells and that these cells override CD44v6-negative cells after cisplatin-treatment. This suggests that tumor expression of CD44v6-containing variants may condition the outcome of GC patients treated with chemotherapy.

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“…2 Inhibitors of signal transducer and activator of transcription-3 (STAT3), a transcription factor that promotes cell survival and proliferation, have been shown to improve the clinical effectiveness of DDP. 3,4 This suggests that targeting the active, phosphorylated form of STAT3, p-STAT3, is a potential strategy for overcoming resistance to DDP-therapy. 4 In normal cells, STAT3 is transiently activated (p-STAT3) for half an hour up to several hours.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 This suggests that targeting the active, phosphorylated form of STAT3, p-STAT3, is a potential strategy for overcoming resistance to DDP-therapy. 4 In normal cells, STAT3 is transiently activated (p-STAT3) for half an hour up to several hours. However, in solid and hematological tumors, STAT3 is commonly overexpressed or constitutively activated, 5 and this phenomenon has been associated with poor overall survival rates in patients with lung cancer.…”

Section: Introductionmentioning

confidence: 99%

<p>ARHGAP6 Promotes Apoptosis and Inhibits Glycolysis in Lung Adenocarcinoma Through STAT3 Signaling Pathway</p>

et al. 2020

CMAR

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Constitutively activated signal transducer and activator of transcription 3 (STAT3) has been linked to cisplatin (DDP)-resistance in a wide range of cancers. Recent work has indicated that Rho GTPase-activating protein 6 (ARHGAP6) promotes cell cycle arrest and apoptosis in cervical and breast cancers. However, the role of ARHGAP6 in lung adenocarcinoma and DDP-resistance remains unknown. Materials and Methods: Bioinformatic analysis, quantitative RT-PCR and IHC staining were used to explore ARHGAP6 expression patterns in The Cancer Genome Atlas (TCGA) dataset and patient samples. Statistical analysis was performed to establish the association of ARHGAP6 expression with the resistance to DDP-based chemotherapy in lung adenocarcinoma patients. Functional assays were then conducted to examine the effect of ARHGAP6 on the apoptosis and glycolysis in DDP-resistant/sensitive A549/DPP cells in vitro. Finally, the effects of ARHGAP6 on the chemosensitivity of DDP were explored in vivo. Results: We show that decreased ARHGAP6 levels are a reliable marker of lung adenocarcinoma across published datasets, cell culture lines, and clinical samples. Low ARHGAP6 expression was linked to decreased apoptosis and increased metabolic activity, which highlights ARHGAP6's role as a tumor suppressor. Furthermore, activated p-STAT3 levels increased dramatically in the absence of ARHGAP6, which suggests that ARHGAP6 can inhibit the STAT3 pathway. In agreement with previous studies that linked p-STAT3 levels to DDP-resistance, our in vitro and in vivo data indicate that tumors became more resistant to DDP-therapy with reduced ARHGAP6 levels and an associated increase in p-STAT3. Conclusion: ARHGAP6 presents a novel study target for overcoming p-STAT3-associated DDP-resistance in lung adenocarcinoma and potentially other cancers.

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Targeting STAT3 inhibition to reverse cisplatin resistance

Cited by 60 publications

References 123 publications

Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

Expression of CD44v6-Containing Isoforms Influences Cisplatin Response in Gastric Cancer Cells

<p>ARHGAP6 Promotes Apoptosis and Inhibits Glycolysis in Lung Adenocarcinoma Through STAT3 Signaling Pathway</p>

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