HSP90 is necessary for the ACK1-dependent phosphorylation of STAT1 and STAT3

Mahendrarajah, Nisintha; Borisova, Marina; Reichardt, Sigrid; Godmann, Maren; Sellmer, Andreas; Mahboobi, Siavosh; Haitel, Andrea; Schmid, Katharina; Kenner, Lukas; Heinzel, Thorsten; Beli, Petra; Krämer, Oliver

doi:10.1016/j.cellsig.2017.07.014

Cited by 35 publications

(25 citation statements)

References 40 publications

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“…STAT3 has been implicated in the development of different human malignancies . Previous studies have confirmed that aberrant constitutive activation of STAT3 is strongly associated with the initiation, maintenance, and progression of various malignancies . Our research team has reported that inhibition of STAT3 phosphorylation has beneficial clinical therapeutic effects on human osteosarcoma.…”

Section: Discussionmentioning

confidence: 78%

“…23 Previous studies have confirmed that aberrant constitutive activation of STAT3 is strongly associated with the initiation, maintenance, and progression of various malignancies. 23,40 Our research team has reported that inhibition of STAT3 phosphorylation has beneficial clinical therapeutic effects on human osteosarcoma. Persistently active STAT3 has been identified in many human cancers and appears to be required for the continued growth or resistance to apoptosis of cultured human cancer cells.…”

Section: Discussionmentioning

confidence: 99%

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Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

et al. 2019

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Osteosarcoma is the most common primary malignant bone tumor. Raddeanin A ( RA ) is an active oleanane‐type triterpenoid saponin extracted from the traditional Chinese herb Anemone raddeana Regel that exerts antitumor activity against several cancer types. However, the effect of RA on osteosarcoma remains unclear. In the present study, we showed that RA inhibited proliferation and induced apoptosis of osteosarcoma cells in a dose‐ and time‐dependent way in vitro and in vivo. RA treatment resulted in excessive reactive oxygen species ( ROS ) generation and JNK and ERK 1/2 activation. Apoptosis induction was evaluated by the activation of caspase‐3, caspase‐8, and caspase‐9 and poly‐ADP ribose polymerase ( PARP ) cleavage. RA ‐induced cell death was significantly restored by the ROS scavenger glutathione ( GSH ), the pharmacological inhibitor of JNK SP 600125, or specific JNK knockdown by sh RNA . Additionally, signal transducer and activator of transcription 3 ( STAT 3) activation was suppressed by RA in human osteosarcoma, and this suppression was restored by GSH , SP 600125, and JNK ‐sh RNA . Further investigation showed that STAT 3 phosphorylation was increased after JNK knockdown. In a tibial xenograft tumor model, RA induced osteosarcoma apoptosis and notably inhibited tumor growth. Taken together, our results show that RA suppresses proliferation and induces apoptosis by modulating the JNK /c‐Jun and STAT 3 signaling pathways in human osteosarcoma. Therefore, RA may be a promising candidate antitumor drug for osteosarcoma intervention.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

et al. 2019

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“…C). Studies have shown that STAT3 is phosphorylated and transferred into the nucleus to regulate gene expression . In other words, the nuclear transfer of STAT3 is an important characteristic of its activation.…”

Section: Resultsmentioning

confidence: 99%

PGD2/PTGDR2 Signaling Restricts the Self-Renewal and Tumorigenesis of Gastric Cancer

Zhang

Bie

et al. 2018

Stem Cells

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The antitumor effect of prostaglandin D2 (PGD2) on gastric cancer (GC) has been known for decades. However, the mechanism of PGD2's control of GC growth is unclear. Cancer stem cells (CSCs) are implicated in tumor neovascularization, invasiveness, and therapeutic resistance. Herein, we discovered that signaling between PGD2 and its receptor (PTGDR2) has the ability to restrict the self-renewal of GC cells in vitro and suppress tumor growth and metastasis in vivo. To obtain these findings, we first determined that PGD2 synthase (L-PTGDS) and PTGDR2 expression were lower in GC tissues than adjacent tissues and was associated with the patients' prognosis. Moreover, the expression of L-PTGDS and PTGDR2 was negatively correlated with the GC-CSC markers Sall4 and Lgr5 in GC tissues. Second, L-PTGDS and PTGDR2 expression were knocked down in CSC-like cells, resulting in enhanced expression of CSC markers and self-renewal ability. Direct PGD2 stimulation and L-PTGDS overexpression produced the opposite effect. Thirdly, PGD2 inhibited tumor growth and incidence rate in a subcutaneous tumor model and suppressed liver and mesenteric metastasis in a peritoneal metastasis model. Interfering with the expression of PTGDR2 reversed these effects in vivo. Last, a mechanistic study found that PGD2 inhibited STAT3 phosphorylation and nuclear expression. Further experiments revealed that the inhibitory effect of PGD2 on the expression of CSC markers disappeared after mutations were introduced into STAT3 phosphorylation (Thr705) site. In short, this study reveals a novel function of PGD2/PTGDR2 signaling on CSC regulation and provides a new way to control the development of GC. Stem Cells 2018;36:990-1003.

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“…Uridine derivative and nucleoside analog in vitro/preclinical/clinical Pancreatic [20] Cancers 2020, 12, 21 3 of 27 [51][52][53][54][55] in vitro 32D mouse hematopoietic cells expressing wild-type BCR-ABL (b3a2, 32Dp210) and mutant BCR-ABL imatinib-resistant cell lines [56] in vitro/preclinical Drug-resistant chronic myelogenous leukemia [57] clinical trial (phase II) Myeloproliferative neoplasms [58] clinical trials (phase I/II) EGFR-mutant lung cancer with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors [59] AUY922, HSP990, PU-H71 -in vitro/preclinical Leukemia [60] Onalespib (AT13387) second-generation, non-ansamycin inhibitor in vitro Transformed kidney cells, primary lung adenocarcinoma [61] in vitro/preclinical Melanoma [62] in vitro/preclinical NSCLC [63] in vitro/preclinical NSCLC [64] XL888…”

Section: Rp101 (Brivudine)mentioning

confidence: 99%

“…Another nonreceptor tyrosine kinase, activated CDC42-associated kinase-1 (ACK1), catalyzes the phosphorylation of STAT1, STAT3, and STAT5. HSP90 interacts with ACK1 [99] and is necessary for the phosphorylation of STAT1 in transformed kidney cells and STAT3 in primary lung adenocarcinoma by ACK1 [61].…”

Section: Ack1mentioning

confidence: 99%

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

Hermetet

Girodon

Jego

2019

Cancers

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While cells from multicellular organisms are dependent upon exogenous signals for their survival, growth, and proliferation, commitment to a specific cell fate requires the correct folding and maturation of proteins, as well as the degradation of misfolded or aggregated proteins within the cell. This general control of protein quality involves the expression and the activity of molecular chaperones such as heat shock proteins (HSPs). HSPs, through their interaction with the STAT3/STAT5 transcription factor pathway, can be crucial both for the tumorigenic properties of cancer cells (cell proliferation, survival) and for the microenvironmental immune cell compartment (differentiation, activation, cytokine secretion) that contributes to immunosuppression, which, in turn, potentially promotes tumor progression. Understanding the contribution of chaperones such as HSP27, HSP70, HSP90, and HSP110 to the STAT3/5 signaling pathway has raised the possibility of targeting such HSPs to specifically restrain STAT3/5 oncogenic functions. In this review, we present how HSPs control STAT3 and STAT5 activation, and vice versa, how the STAT signaling pathways modulate HSP expression. We also discuss whether targeting HSPs is a valid therapeutic option and which HSP would be the best candidate for such a strategy.

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HSP90 is necessary for the ACK1-dependent phosphorylation of STAT1 and STAT3

Cited by 35 publications

References 40 publications

Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

PGD2/PTGDR2 Signaling Restricts the Self-Renewal and Tumorigenesis of Gastric Cancer

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

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