Hsp90 inhibitor induces KG-1a cell differentiation and apoptosis via Akt/NF-κB signaling

Qin, Jinhong; Wang, Kun; Fu, Xinlu; Zhou, Pengjun; Liu, Zhong; Xu, Dandan; Wang, Yifei; Yang, Dan; Xie, Qiuling; Liu, Qiuying

doi:10.3892/or.2017.5797

Cited by 11 publications

(9 citation statements)

References 39 publications

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“…HSP90AB1, also recognized as HSP90 beta, is a member of the HSP90 family which includes HSP90 alpha (HSP90AA1) and HSP90 beta. HSP90 proteins play an important role in cell regulation, forming complexes with various transcription factors, cellular kinases, and some molecules [30][31][32]. In this study, we have discovered the effect of the interaction between HSP90AB1 and the CC domain on Bcr-Abl cytoplasm localization and its function in chronic myeloid leukemia cells.…”

Section: Introductionmentioning

confidence: 89%

Effect of HSP90AB1 and CC Domain Interaction on Bcr-Abl Protein Cytoplasm Localization and Function in Chronic Myeloid Leukemia Cells

Peng

Huang

Zhou

et al. 2021

Preprint

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Background: The fusion oncoprotein Bcr-Abl is mostly located in the cytoplasm, which causes chronic myeloid leukemia (CML). After moving into the nucleus, the fusion protein can induce apoptosis of CML cells. The coiled-coil domain (CC domain) of Bcr-Abl protein plays a central role in the subcellular localization. However, how CC domain affects subcellular localization of Bcr-Abl remains unclear. Methods: Herein, the key proteins interacting with the Bcr-Abl CC domain were screened by immunoprecipitation binding mass spectrometry. The specific site of Bcr-Abl CC domain binding to target protein was predicted by Deep Viewer. Immunoprecipitation assay was used to confirmed the specific sites of protein binding. IF and western blot were used to observe the subcellular localization of target protein. Western blot was used to examine the protein changes. CCK-8, clonal formation test and FCM cycle detection were used to observe the effect of inhibitor on the proliferation ability of CML cells. FCM apoptosis detection was used to observe the level of cells apoptosis.Results: HSP90AB1 interacts with Bcr-Abl CC domain via N-terminal domain (NTD), preventing the transport of Bcr-Abl protein to the nucleus and maintaining the activation of Bcr-Abl tyrosine kinase. The nucleus-entrapped Bcr-Abl markedly inhibits the proliferation and induces apoptosis of CML cells by activating p73 and repressing the expression of cytoplasmic oncogenic signaling pathways mediated by Bcr-Abl. Moreover, the combination of 17AAG (Tanespimycin) with Leptomycin B (LMB) considerably decreased the proliferation of CML cells.Conclusion: Our study provides evidence that it is feasible to transport Bcr-Abl into the nucleus as an alternative strategy for the treatment of CML, and targeting the NTD of HSP90AB1 to inhibit the interaction with Bcr-Abl is more accurate for the development and application of HSP90 inhibitor in the treatment of CML and other Bcr-Abl-addicted malignancies.

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Section: Introductionmentioning

confidence: 89%

Effect of HSP90AB1 and CC Domain Interaction on Bcr-Abl Protein Cytoplasm Localization and Function in Chronic Myeloid Leukemia Cells

Peng

Huang

Zhou

et al. 2021

Preprint

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“…SNX-2112 was synthesized as previously described in our lab with >98.0% purity [42], dissolved in dimethyl sulfoxide (DMSO) to obtain a 100 mM stock solution, and stored at −20°C. TRAIL was purchased from Merck Millipore (Waltham, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway

Wang

Chen

et al. 2019

Oxidative Medicine and Cellular Longevity

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell apoptosis-inducing factor that can induce apoptosis in a variety of cancer cells. However, resistance to TRAIL in cancer cells is a huge obstacle in creating effective TRAIL-targeted clinical therapies. Thus, agents that can either enhance the effect of TRAIL or overcome its resistance are needed. In this study, we combined TRAIL with SNX-2112, an Hsp90 inhibitor we previously developed, to explore the effect and mechanism that SNX-2112 enhanced TRAIL-induced apoptosis in cervical cancer cells. Our results showed that SNX-2112 markedly enhanced TRAIL-induced cytotoxicity in HeLa cells, and this combination was found to be synergistic. Additionally, we found that SNX-2112 sensitized TRAIL-mediated apoptosis caspase-dependently in TRAIL-resistant HeLa cells. Mechanismly, SNX-2112 downregulated antiapoptosis proteins, including Bcl-2, Bcl-XL, and FLIP, promoted the accumulation of reactive oxygen species (ROS), and increased the expression levels of p-JNK and p53. ROS scavenger NAC rescued SNX-2112/TRAIL-induced apoptosis and suppressed SNX-2112-induced p-JNK and p53. Moreover, SNX-2112 induced the upregulation of death-receptor DR5 in HeLa cells. The silencing of DR5 by siRNA significantly decreased cell apoptosis by the combined effect of SNX-2112 and TRAIL. In addition, SNX-2112 inhibited the Akt/mTOR signaling pathway and induced autophagy in HeLa cells. The blockage of autophagy by bafilomycin A1 or Atg7 siRNA abolished SNX-2112-induced upregulation of DR5. Meanwhile, ROS scavenger NAC, JNK inhibitor SP600125, and p53 inhibitor PFTα were used to verify that autophagy-mediated upregulation of DR5 was regulated by the SNX-2112-stimulated activation of the ROS-JNK-p53 signaling pathway. Thus, the combination of SNX-2112 and TRAIL may provide a novel strategy for the treatment of human cervical cancer by overcoming cellular mechanisms of apoptosis resistance.

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“…Sato et al [46] reported that Akt forms a complex with HSP90, and that inhibition of Akt-HSP90 binding leads to dephosphorylation and inactivation of Akt. It was further reported that inhibition of HSP90 induces differentiation in myeloid cells, and that low concentrations of an HSP90 inhibitor, SNX-2112, arrest cells in the G2/M phase and induce their differentiation and apoptosis, possibly by suppressing Akt and inhibitor of κB kinase, a component of the nuclear factor-κB signaling pathway [47].…”

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

Kinase Inhibitors and Interferons as Other Myeloid Differentiation Inducers in Leukemia Therapy

Takahashi¹

2021

Acta Haematol

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Differentiation therapy using all-<i>trans</i> retinoic acid (ATRA) is well established for the treatment of acute promyelocytic leukemia (APL). Several attempts have been made to treat non-APL acute myeloid leukemia (AML) patients by employing differentiation inducers, such as hypomethylating agents and low-dose cytarabine, with encouraging results. In the present review, I focus on other possible differentiation inducers: kinase inhibitors and interferons (IFNs). A number of kinase inhibitors have been reported to induce differentiation, including CDK inhibitors, GSK3 inhibitors, Akt inhibitors, p38 MAPK inhibitors, Src family kinase inhibitors, Syk inhibitors, mTOR inhibitors, and HSP90 inhibitors. Other powerful inducers are IFNs, which were reported to enhance differentiation with ATRA. Although clinical trials for these kinase modulators remain scarce, their mechanisms of action have been, at least partly, clarified. The Raf/MEK/ERK MAPK pathway and the RARα downstream are affected by many of the kinase inhibitors and IFNs and seem to play a pivotal role for the induction of myeloid differentiation. Further clarification of the mechanisms, as well as the establishment of efficient combination therapies with the kinase inhibitors or IFNs, may lead to the development of effective therapeutic strategies for AML.

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Hsp90 inhibitor induces KG-1a cell differentiation and apoptosis via Akt/NF-κB signaling

Cited by 11 publications

References 39 publications

Effect of HSP90AB1 and CC Domain Interaction on Bcr-Abl Protein Cytoplasm Localization and Function in Chronic Myeloid Leukemia Cells

Effect of HSP90AB1 and CC Domain Interaction on Bcr-Abl Protein Cytoplasm Localization and Function in Chronic Myeloid Leukemia Cells

Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway

Kinase Inhibitors and Interferons as Other Myeloid Differentiation Inducers in Leukemia Therapy

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Hsp90 inhibitor induces KG-1a cell differentiation and apoptosis via Akt/NF-κB signaling

Cited by 11 publications

References 39 publications

Effect of HSP90AB1&nbsp;and CC&nbsp;Domain Interaction on Bcr-Abl&nbsp;Protein Cytoplasm Localization and Function in Chronic Myeloid Leukemia Cells

Effect of HSP90AB1&nbsp;and CC&nbsp;Domain Interaction on Bcr-Abl&nbsp;Protein Cytoplasm Localization and Function in Chronic Myeloid Leukemia Cells

Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway

Kinase Inhibitors and Interferons as Other Myeloid Differentiation Inducers in Leukemia Therapy

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Effect of HSP90AB1 and CC Domain Interaction on Bcr-Abl Protein Cytoplasm Localization and Function in Chronic Myeloid Leukemia Cells

Effect of HSP90AB1 and CC Domain Interaction on Bcr-Abl Protein Cytoplasm Localization and Function in Chronic Myeloid Leukemia Cells