The Quinone Methide Aurin Is a Heat Shock Response Inducer That Causes Proteotoxic Stress and Noxa-dependent Apoptosis in Malignant Melanoma Cells

Davis, Angela; Qiao, Shuxi; Lesson, Jessica L.; Vega, Montserrat Rojo de la; Park, Sophia; Seanez, Carol; Gokhale, Vijay; Cabello, Christopher M.; Wondrak, Georg T.

doi:10.1074/jbc.m114.592626

Cited by 26 publications

(43 citation statements)

References 68 publications

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“…Further analysis of the potential roles of these genes revealed that the majority of them is known to be induced as a result of an unfolded protein response (UPR), leading to proteotoxic stress [36]. In addition, we found that the pro-apoptotic genes PMAIP1 (Noxa) [37] and CHAC1 [38] were up-regulated by both P1 (20.7-fold and 51.3-fold, respectively) and P2 (14.5-fold and 31.1-fold, respectively).…”

Section: Resultsmentioning

confidence: 99%

“…3), and believed to be important in the induction of cell death and proliferation, were further examined by RT-qPCR in HL-60 and Ramos cells. Of these genes, ATF3 and HMOX1 are involved in the unfolded protein response [36], PMAIP1 and CHAC1 in the induction of the intrinsic apoptosis pathway [38, 45] and MYC in cell proliferation and immortalization [39] (Fig. 5a, b).…”

Section: Resultsmentioning

confidence: 99%

“…These genes are involved in the heat shock response, which is used by cancer cells to alleviate stress [18]. HMOX1, HSPA6 and HSPA1A have been shown to be induced after proteotoxic stress [36]. Due to the relationship between proteotoxic stress and the UPR, we further investigated differentially regulated genes involved in the UPR.…”

Section: Discussionmentioning

confidence: 99%

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Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones

et al. 2018

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Purpose Previously, compounds containing a piperidone structure have been shown to be highly cytotoxic to cancer cells. Recently, we found that the piperidone compound P2 exhibits a potent anti-neoplastic activity against human breast cancer-derived cells. Here, we aimed to evaluate two piperidone compounds, P1 and P2, for their potential anti-neoplastic activity against human leukemia/lymphoma-derived cells. Methods Cytotoxicity and apoptosis induction were evaluated using MTS, annexin V-FITC/PI and mitochondrial membrane potential polychromatic assays to confirm the mode of action of the piperidone compounds. The effects of compound P1 and P2 treatment on gene expression were assessed using AmpliSeq analysis and, subsequently, confirmed by RT-qPCR and Western blotting. Results We found that the two related piperidone compounds P1 and P2 selectively killed the leukemia/lymphoma cells tested at nanomolar concentrations through induction of the intrinsic apoptotic pathway, as demonstrated by mitochondrial depolarization and caspase-3 activation. AmpliSeq-based transcriptome analyses of the effects of compounds P1 and P2 on HL-60 acute leukemia cells revealed a differential expression of hundreds of genes, 358 of which were found to be affected by both. Additional pathway analyses revealed that a significant number of the common genes were related to the unfolded protein response, implying a possible role of the two compounds in the induction of proteotoxic stress. Subsequent analyses of the transcriptome data revealed that P1 and P2 induced similar gene expression alterations as other well-known proteasome inhibitors. Finally, we found that Noxa, an important mediator of the activity of proteasome inhibitors, was significantly upregulated at both the mRNA and protein levels, indicating a possible role in the cytotoxic mechanism induced by P1 and P2. Conclusions Our data indicate that the cytotoxic activity of P1 and P2 on leukemia/lymphoma cells is mediated by proteasome inhibition, leading to activation of pro-apoptotic pathways.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones

et al. 2018

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“…Proteotoxic stress is emerging as an attracting druggable response. Malignant cells exhibit higher levels of proteotoxic stress, as a consequence of their higher proliferative and mutational status [35–38]. This peculiarity renders cancer cells more dependent on the UPS and more vulnerable to its inhibitors or to inducers of proteotoxic stress [39, 40].…”

Section: Discussionmentioning

confidence: 99%

The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells

et al. 2016

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Relapse after treatment is a common and unresolved problem for patients suffering of the B-cell chronic lymphocytic leukemia (B-CLL). Here we investigated the ability of the isopeptidase inhibitor 2cPE to trigger apoptosis in leukemia cells in comparison with bortezomib, another inhibitor of the ubiquitin-proteasome system (UPS). Both inhibitors trigger apoptosis in CLL B cells and gene expression profiles studies denoted how a substantial part of genes up-regulated by these compounds are elements of adaptive responses, aimed to sustain cell survival. 2cPE treatment elicits the up-regulation of chaperones, proteasomal subunits and elements of the anti-oxidant response. Selective inhibition of these responses augments apoptosis in response to 2cPE treatment. We have also observed that the product of the ataxia telangiectasia mutated gene (ATM) is activated in 2cPE treated cells. Stimulation of ATM signaling is possibly dependent on the alteration of the redox homeostasis. Importantly ATM inhibition, mutations or down-modulation increase cell death in response to 2cPE. Overall this work suggests that 2cPE could offer new opportunities for the treatment of B-CLL.

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“…HSF1 could influence some molecular chaperones, which serve to regulate some heat shock responses [28]. The heat shock responses have been confirmed to be related to a variety of cellular functions, including protein folding, signal transduction, immunity and apoptosis [29][30][31]. Thus, we inferred that DHCE has a potent anti-tumor effect.…”

Section: Discussionmentioning

confidence: 84%

Dihydrocelastrol inhibits multiple myeloma cell proliferation and promotes apoptosis through ERK1/2 and IL-6/STAT3 pathways <italic>in vitro</italic> and <italic>in vivo</italic>

et al. 2017

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Multiple myeloma (MM) is the second most frequent malignant hematological disease. Dihydrocelastrol (DHCE) is synthesized by hydrogenated celastrol, a treterpene isolated from Chinese medicinal plant Tripterygium regelii. In this study, we first reported the anti-tumor activity of DHCE on MM cells. We found that DHCE could inhibit cell proliferation and promote apoptosis through caspase-dependent way in vitro. In addition, DHCE could inactivate the expression of interleukin (IL)-6 and downregulate the phosphorylation of extracellular regulated protein kinases (ERK1/2) and the signal transducer and activator of transcription 3 (STAT3) in MM. It also retained its activity against MM cell lines in the presence of IL-6. Furthermore, treatment of MM cells with DHCE resulted in an accumulation of cells in G0/G1 phase of the cell cycle. Notably, DHCE reduced the expression of cyclin D1 and cyclin-dependent kinases 4 and 6 in MM cell lines. Additionally, its efficacy toward the MM cell lines could be enhanced in combination with the histone deacetylase inhibitor panobinostat (LBH589), which implied the possibility of the combination treatment of DHCE and LBH589 as a potential therapeutic strategy in MM. In addition, treatment of NCI-H929 tumor-bearing nude mice with DHCE (10 mg/kg/d, i.p., 1-14 days) resulted in 73% inhibition of the tumor growth in vivo. Taken together, the results of our present study indicated that DHCE could inhibit cellular proliferation and induce cell apoptosis in myeloma cells mediated through different mechanisms, possibly through inhibiting the IL-6/STAT3 and ERK1/2 pathways. And it may provide a new therapeutic option for MM patients.

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The Quinone Methide Aurin Is a Heat Shock Response Inducer That Causes Proteotoxic Stress and Noxa-dependent Apoptosis in Malignant Melanoma Cells

Cited by 26 publications

References 68 publications

Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones

Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones

The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells

Dihydrocelastrol inhibits multiple myeloma cell proliferation and promotes apoptosis through ERK1/2 and IL-6/STAT3 pathways <italic>in vitro</italic> and <italic>in vivo</italic>

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The Quinone Methide Aurin Is a Heat Shock Response Inducer That Causes Proteotoxic Stress and Noxa-dependent Apoptosis in Malignant Melanoma Cells

Cited by 26 publications

References 68 publications

Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones

Induction of apoptosis via proteasome inhibition in leukemia/lymphoma cells by two potent piperidones

The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells

Dihydrocelastrol inhibits multiple myeloma cell proliferation and promotes apoptosis through ERK1/2 and IL-6/STAT3 pathways &lt;italic&gt;in vitro&lt;/italic&gt; and &lt;italic&gt;in vivo&lt;/italic&gt;

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Dihydrocelastrol inhibits multiple myeloma cell proliferation and promotes apoptosis through ERK1/2 and IL-6/STAT3 pathways <italic>in vitro</italic> and <italic>in vivo</italic>