The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma

Chatterjee, Manik; Andrulis, Mindaugas; Stühmer, Thorsten; Müller, Elisabeth; Hofmann, Claudia; Steinbrunn, Torsten; Heimberger, Tanja; Schraud, Heike; S, Kreßmann; Einsele, Hermann; Bargou, Ralf C.

doi:10.3324/haematol.2012.066175

Cited by 139 publications

(157 citation statements)

References 39 publications

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“…Recently, it has been reported that pharmacologic inhibition of HSP70 (albeit at high concentrations) can result in synergistic improvements in the cytotoxic activity of the HSP90 inhibitor NVP-AUY922 in multiple myeloma cells (26). More significantly, the findings of Zaarur and colleagues are of direct relevance to the data we are reporting here (27).…”

Section: Discussionsupporting

confidence: 75%

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Acquaviva

Sang

et al. 2014

Molecular Cancer Research

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Because of their pleiotropic effects on critical oncoproteins, inhibitors of HSP90 represent a promising new class of therapeutic agents for the treatment of human cancer. However, pharmacologic inactivation of HSP90 subsequently triggers a heat shock response that may mitigate the full therapeutic benefit of these compounds. To overcome this limitation, a clinically feasible method was sought to block HSP synthesis induced by the potent HSP90 inhibitor ganetespib. An immunoassay screen of 322 late-stage or clinically approved drugs was performed to uncover compounds that could block upregulation of the stress-inducible HSP70 that results as a consequence of HSP90 blockade. Interestingly, inhibitors of the phosphoinositide 3-kinase (PI3K)/mTOR class counteracted ganetespibinduced HSP70 upregulation at both the gene and protein level by suppressing nuclear translocation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. This effect was conserved across multiple tumor types and was found to be regulated, in part, by mTOR-dependent translational activity. Pretreatment with cycloheximide, PI3K/mTOR inhibitor, or an inhibitor of eIF4E (a translation initiation factor and downstream effector of mTOR) all reduced ganetespib-mediated nuclear HSF1 accumulation, indicating that mTOR blockade confers a negative regulatory effect on HSF1 activity. Moreover, combined therapy regimens with mTOR or dual PI3K/mTOR inhibitors potentiated the antitumor efficacy of ganetespib in multiple in vivo models.

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Section: Discussionsupporting

confidence: 75%

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Acquaviva

Sang

et al. 2014

Molecular Cancer Research

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“…in this regard, Pi3K/mTOR inhibitor in combination with NVP-Hsp990 mentioned above, rendered the Hsp90 blockade-mediated stress response ineffective and considerably increased the anti-multiple myeloma toxicity (118). Similarly, Chatterjee et al (119) demonstrated that the knockdown of Hsp72 and/or Hsp73 or treatment with VER-155008, decreased protein levels of Hsp90-chaperone clients affecting multiple oncogenic signaling pathways, and acted synergistically with the novel Hsp90 inhibitor NVP-AUY922 in myeloma cell death induction. Inhibition of the Pi3K/Akt/GSK3β pathway with siRNA or PI103 decreased expression of the heat shock transcription factor 1 and downregulated constitutive and inducible Hsp70 expression (119).…”

Section: Combination Of Hsp90 Inhibitor With Second Therapymentioning

confidence: 99%

“…Similarly, Chatterjee et al (119) demonstrated that the knockdown of Hsp72 and/or Hsp73 or treatment with VER-155008, decreased protein levels of Hsp90-chaperone clients affecting multiple oncogenic signaling pathways, and acted synergistically with the novel Hsp90 inhibitor NVP-AUY922 in myeloma cell death induction. Inhibition of the Pi3K/Akt/GSK3β pathway with siRNA or PI103 decreased expression of the heat shock transcription factor 1 and downregulated constitutive and inducible Hsp70 expression (119). Moreover, NVP-AUY922 in combination with histone deacetylase inhibitors SAHA, NVP-LBH589, melphalan or doxorubicin resulted in synergistic inhibition of viability, with strong synergy (combination index <0.3) in the case of melphalan.…”

Section: Combination Of Hsp90 Inhibitor With Second Therapymentioning

confidence: 99%

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

Solárová¹,

Mojžiš²,

Solár³

2014

Int J Oncol

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Abstract. Hsp90 is a molecular chaperone that maintains the structural and functional integrity of various client proteins involved in signaling and many other functions of cancer cells. The natural inhibitors, ansamycins influence the Hsp90 chaperone function by preventing its binding to client proteins and resulting in their proteasomal degradation. Nand C-terminal inhibitors of Hsp90 and their analogues are widely tested as potential anticancer agents in vitro, in vivo as well as in clinical trials. It seems that Hsp90 competitive inhibitors target different tumor types at nanomolar concentrations and might have therapeutic benefit. On the contrary, some Hsp90 inhibitors increased toxicity and resistance of cancer cells induced by heat shock response, and through the interaction of survival signals, that occured as side effects of treatments, could be very effectively limited via combination of therapies. The aim of our review was to collect the data from experimental and clinical trials where Hsp90 inhibitor was combined with other therapies in order to prevent resistance as well as to potentiate the cytotoxic and/or antiproliferative effects.

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“…HSP70, as one of the HSPs, is an ATP-dependent molecular chaperone which performs house-keeping functions; controlling the activity, turnover and trafficking of a variety of proteins, including protein kinases, steroid receptors and transcription factors. HSP70 exhibits an important role in various signaling pathways that have crucial roles in growth control, cell survival and developmental processes (6,7). However, the role of HSP70 in the HG-induced EMT of peritoneal mesothelial cells is unknown.…”

Section: Introductionmentioning

confidence: 99%

HSP70 inhibits high glucose-induced Smad3 activation and attenuates epithelial-to-mesenchymal transition of peritoneal mesothelial cells

Bao

Hao

et al. 2014

Molecular Medicine Reports

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Abstract. Heat shock proteins (HSPs) are molecular chaperones that were initially identified as proteins expressed following exposure of cells to environmental stress. However, the function of HSPs in epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells remains unknown. In the present study, the regulation of HSPs and their function in cell EMT, particularly in rat peritoneal mesothelial cells (RPMCs), and the surrounding glucose concentrations and the molecular mechanism involved were investigated. This study explored the effect of HSP70 on high glucose (HG)-induced EMT by overexpression and small interfering RNA (siRNA) knockdown of HSP70, as well as the underlying molecular mechanisms. It was found that HSP70 inhibits HG-induced EMT by modulating Smad expression and activation. HSP70 overexpression inhibited phosphorylation and nuclear translocation of p-Smad3 and p-Smad4, while siRNA of HSP70 enhanced HG-induced Smad3 and Smad4 phosphorylation and EMT. Furthermore, HSP70 suppressed EMT by inhibiting the generation of reactive oxygen species (ROS) induced by HG. In conclusion, HSP70 inhibits EMT of peritoneal mesothelial cells primarily by exerting domain-specific effects on Smad3 and Smad4 activation and reducing the release of ROS. HSP70 may be a novel therapeutic target for peritoneal dialysis patients with peritoneal fibrosis.

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The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma

Cited by 139 publications

References 39 publications

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

HSP70 inhibits high glucose-induced Smad3 activation and attenuates epithelial-to-mesenchymal transition of peritoneal mesothelial cells

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