Up-regulation of Heat Shock Protein 27 Induces Resistance to 17-Allylamino-Demethoxygeldanamycin through a Glutathione-Mediated Mechanism

McCollum, Andrea K.; TenEyck, Cynthia J.; Sauer, Brian M.; Toft, David O.; Erlichman, Charles

doi:10.1158/0008-5472.can-06-1629

Cited by 151 publications

(161 citation statements)

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“…We observed a significant increase in hsp22, hsp27, and hsp70 expression in the flies that were exposed to DCA up to 48 h. However, in flies that were exposed to DCA for a prolonged period, hsp27 expression was significantly upregulated in 30-50-dayold organism. hsp27 is reported to maintain cellular redox by upholding intracellular glutathione (Arrigo et al 2005;Concannon et al 2003;McCollum et al 2006) and by suppressing ROS generation (Liu et al 2007;Wyttenbach et al 2002). In agreement with the above discussion, we observed decreased ROS generation and GSH depletion concurrent with increased hsp27 expression in DCA-exposed aged flies which was further evident by a significant positive correlation drawn between hsp27 expression and GSH content (Y GSH =0.592 hsp27 +0.341, r=0.847, P=0.033) and a Fig.…”

Section: Discussionsupporting

confidence: 90%

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

Pandey

Vimal

Chandra

et al. 2014

AGE

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Dichloroacetic acid (DCA), a water disinfection by-product, has attained emphasis due to its prospect for clinical use against different diseases including cancer along with negative impact on organisms. However, these reports are based on the toxicological as well clinical data using comparatively higher concentrations of DCA without much of environmental relevance. Here, we evaluate cellular as well as organismal effects of DCA at environmentally and mild clinically relevant concentrations (0.02-20.0 μg/ml) using an established model organism, Drosophila melanogaster. Flies were fed on food mixed with test concentrations of DCA for 12-48 h to examine the induction of reactive oxygen species (ROS) generation, oxidative stress (OS), heat shock genes (hsps) and cell death along with organismal responses. We also examined locomotor performance, ROS generation, glutathione (GSH) depletion, expression of GSH-synthesizing genes (gclc and gclm), and hsps at different days (0, 10, 20, 30, 40, 50) of the age in flies after prolonged DCA exposure. We observed mild OS and induction of antioxidant defense system in 20.0 μg/ml DCA-exposed organism after 24 h. After prolonged exposure to DCA, exposed organism exhibited improved survival, elevated expression of hsp27, gclc, and gclm concomitant with lower ROS generation and GSH depletion and improved locomotor performance. Conversely, hsp27 knockdown flies exhibited reversal of the above end points. The study provides evidence for the attenuation of cellular and functional decline in aged Drosophila after prolonged DCA exposure and the effect of hsp27 modulation which further incites studies towards the therapeutic application of DCA.

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Section: Discussionsupporting

confidence: 90%

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

Pandey

Vimal

Chandra

et al. 2014

AGE

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“…The role of MSCV integration in making the cells more viable in the presence of GA remains unclear, although we did observe a slightly enhanced amount of total glutathione (data not shown). This may account for resistance of the MSCV cells to geldanamycin based on a previous study which showed a correlation between increased glutathione levels and resistance of cells to Hsp90 inhibitors [22].…”

Section: Resultsmentioning

confidence: 85%

Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context

Theodoraki

Kunjappu

Sternberg

et al. 2007

Experimental Cell Research

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Hsp90 inhibitors are currently in clinical trials for cancer therapy based on their ability to promote proteasomal degradation of oncogenic protein kinases and nuclear receptors. Results from recent studies suggest that cancer cells are more sensitive to these inhibitors than cells from healthy tissues. We analyzed an immortalized cell line Ba/F3, for sensitivity to the Hsp90 inhibitor geldanamycin in the absence and presence of the oncogenic tyrosine fusion kinase NPM-ALK expressed from a retroviral vector. Our results showed that NPM-ALK expression makes Akt and Cdk4 more resistant to degradation in the presence of geldanamycin, and there was a slightly reduced amount of apoptosis. The mechanism underlying the effect of NPM-ALK on Akt stability was probed by comparison of the turnover of the kinase after translation inhibition and geldanamycin treatment. We observed that Akt was degraded more rapidly in the presence of GA than upon translation inhibition without NPM-ALK expression. This suggests that NPM-ALK protects the mature kinase. Furthermore, Akt failed to bind to the Cdc37 chaperone in cells expressing NPMALK, which also correlates with increased Akt stability.

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“…Thus, it is likely that STAT5 modulates expression or activity of these enzymes via an indirect effect on Hsp27 and Hsp70 expression. 43,44 In addition to these proteins, DJ-1, originally identified as an oncogene product, is a protein with anti-apoptotic activity and its main action is to protect cells from oxidative stress. 33 DJ-1 plays a major role in the removal of hydrogen peroxide, a powerful oxidant 33 and in the protection against oxidative stress by increasing intracellular levels of GSH and Hsp70.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

Cholez

Debuysscher

Bourgeais³

et al. 2012

Leukemia

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,5,6 STAT5 transcription factors are involved in normal B lymphocyte development and in leukemogenesis. We show that the inhibition of STAT5A expression or activity in the NALM6, 697 and Reh leukemic pre-B cell lines, results in a higher spontaneous apoptosis and an increased FAS-induced cell death. However, the molecular mechanisms underlying the altered pre-B cell survival are unclear. We used a proteomic approach to identify proteins that are differentially regulated in cells expressing (NALM6D5A) or not a dominant negative form of STAT5A. Among the 14 proteins identified, six were involved in the control of the oxidative stress like glutathione (GSH) synthetase and DJ-1. Accordingly, we showed increased levels of reactive oxygen species (ROS) in NALM6D5A cells and suppression of the increased sensitivity to Fas-mediated apoptosis by the GSH tripeptide. Similar results were observed when NALM6 cells were treated with TAT-STAT5D5A fusion proteins or STAT5A shRNA. In addition, the 697 and Reh pre-B cells were found to share number of molecular changes observed in NALM6D5A cells including ROS generation, following inhibition of STAT5 expression or function. Our results point out to a hitherto undescribed link between STAT5 and oxidative stress and provide new insights into STAT5 functions and their roles in leukemogenesis.Leukemia ( INTRODUCTIONThe signal transducer and activator of transcription factors STAT5A and STAT5B are two closely related STAT family members that play a major role in cytokine and growth factor signaling. 1 Number of studies have demonstrated that STAT5 plays a crucial role in hematopoiesis. In particular, the knockout mice models (Stat5a/ b DN/DN and Stat5a/b null/null ) have pointed up the important role of STAT5 in hematopoietic cell development. 2,3 These mice have multiple hematopoietic defects, which affect the proliferation and/ or survival of both myeloid and lymphoid lineages, including B-cell development. 4 In the Stat5a/b null/null mice, the precursor B-cell compartment is substantially reduced presumably due to an inability of progenitor B cells to proliferate in response to interleukin-7 (IL-7). However, differentiation towards mature B cells seems to be unaffected. 5,6 STAT5 is also involved in the regulation of IL-7-dependent germline transcription, histone acetylation and DNA recombination of distal VH gene segments, which are the hallmark of B lymphocyte development. 7 Accordingly, a constitutively active form of STAT5B in IL-7R À / À mice, is sufficient to restore B-cell development. 8 However, the instructive role for STAT5 and IL-7-R signaling in early B-cell development has been controversial in a mouse model of conditional mutagenesis of STAT5. 9 This model showed that the main role of IL-7-mediated activation of STAT5 is to promote pro-B-cell survival via Mcl1 and to prevent premature rearrangements of the immunoglobulin-k light-chain locus (Igk) by binding to the

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Up-regulation of Heat Shock Protein 27 Induces Resistance to 17-Allylamino-Demethoxygeldanamycin through a Glutathione-Mediated Mechanism

Abstract: 17-Allylamino-demethoxygeldanamycin (17-AAG), currently in phase I and II clinical trials as an anticancer agent, binds to the ATP pocket of heat shock protein (Hsp90).

Cited by 151 publications

References 49 publications

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

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