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Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia-lymphoma cells.

Taniguchi H, Hasegawa H, Sasaki D, Ando K, Sawayama Y, Imanishi D, Taguchi J, Imaizumi Y, Hata T, Tsukasaki K, Uno N, Morinaga Y, Yanagihara K, Miyazaki Y - Cancer Sci. (2014)

Bottom Line: AUY922 caused strong upregulation of HSP70, a surrogate marker of HSP90 inhibition, and a dose-dependent decrease in HSP90 client proteins associated with cell survival, proliferation, and cell cycle in the G1 phase, including phospho-Akt, Akt, IKKα, IKKβ, IKKγ, Cdk4, Cdk6, and survivin.In fact, SGI-1776, a pan-PIM kinase inhibitor, successfully inhibited the growth of primary ATL cells as well as ATL-related cell lines.Our findings suggest that AUY922 is an effective therapeutic agent for ATL, and PIM kinases may be a novel therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Department of Hematology, Sasebo City General Hospital, Sasebo, Japan; Atomic Bomb Disease and Hibakusha Medicine Unit, Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

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Effects of heat shock protein (HSP) 90 inhibitor AUY922 on HSP90, HSP70, and HSP90 client proteins. Western blot analysis revealed that AUY922 treatment led to strong upregulation of HSP70, a surrogate marker of HSP90 inhibition. In addition, dose-dependent decreases in HSP90 client proteins associated with cell survival, proliferation, and cell cycle, including phospho-Akt (p-Akt), Akt, IκB kinase (IKK)α, IKKβ, IKKγ (a), and Cdk4, Cdk6, and survivin (b), were seen.
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fig05: Effects of heat shock protein (HSP) 90 inhibitor AUY922 on HSP90, HSP70, and HSP90 client proteins. Western blot analysis revealed that AUY922 treatment led to strong upregulation of HSP70, a surrogate marker of HSP90 inhibition. In addition, dose-dependent decreases in HSP90 client proteins associated with cell survival, proliferation, and cell cycle, including phospho-Akt (p-Akt), Akt, IκB kinase (IKK)α, IKKβ, IKKγ (a), and Cdk4, Cdk6, and survivin (b), were seen.

Mentions: To verify the molecular mechanisms of the effects of AUY922 on survival and apoptosis of ATL-related cell lines, we examined the expressions of HSP90, HSP70, and several intracellular regulators of cell proliferation, cell cycle, and apoptosis, including p-Akt, Akt, IκBα, IKKα, IKKβ, IKKγ, Cdk4, Cdk6, Bcl-2, and survivin. AUY922 treatment led to induction of HSP70, a surrogate marker for inhibition of HSP90 function, but did not influence the protein level of HSP90 itself. HSP90 and its co-chaperones modulate tumor cell apoptosis, and much of their activity seems to be mediated through effects on the PI3K/Akt pathway and NF-κB function. Suppression of HSP90 function by AUY922 decreases the level of Akt, resulting in a reduction of activated p-Akt. The IKK complex, composed of IKKα, IKKβ, and IKKγ, is a positive regulator of NF-κB. In general, a decrease in the IKK complex inhibits phosphorylation of IκBα, resulting in its increased level. In the present study, AUY922 treatment decreased expression of the IKK complex in all tested cell lines. Among the apoptosis-related proteins examined, we found a decrease in survivin. Overall, we found similar changes in HSP90 client proteins regardless of the presence of wild-type or mutant p53 (Fig. 5).


Heat shock protein 90 inhibitor NVP-AUY922 exerts potent activity against adult T-cell leukemia-lymphoma cells.

Taniguchi H, Hasegawa H, Sasaki D, Ando K, Sawayama Y, Imanishi D, Taguchi J, Imaizumi Y, Hata T, Tsukasaki K, Uno N, Morinaga Y, Yanagihara K, Miyazaki Y - Cancer Sci. (2014)

Effects of heat shock protein (HSP) 90 inhibitor AUY922 on HSP90, HSP70, and HSP90 client proteins. Western blot analysis revealed that AUY922 treatment led to strong upregulation of HSP70, a surrogate marker of HSP90 inhibition. In addition, dose-dependent decreases in HSP90 client proteins associated with cell survival, proliferation, and cell cycle, including phospho-Akt (p-Akt), Akt, IκB kinase (IKK)α, IKKβ, IKKγ (a), and Cdk4, Cdk6, and survivin (b), were seen.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317953&req=5

fig05: Effects of heat shock protein (HSP) 90 inhibitor AUY922 on HSP90, HSP70, and HSP90 client proteins. Western blot analysis revealed that AUY922 treatment led to strong upregulation of HSP70, a surrogate marker of HSP90 inhibition. In addition, dose-dependent decreases in HSP90 client proteins associated with cell survival, proliferation, and cell cycle, including phospho-Akt (p-Akt), Akt, IκB kinase (IKK)α, IKKβ, IKKγ (a), and Cdk4, Cdk6, and survivin (b), were seen.
Mentions: To verify the molecular mechanisms of the effects of AUY922 on survival and apoptosis of ATL-related cell lines, we examined the expressions of HSP90, HSP70, and several intracellular regulators of cell proliferation, cell cycle, and apoptosis, including p-Akt, Akt, IκBα, IKKα, IKKβ, IKKγ, Cdk4, Cdk6, Bcl-2, and survivin. AUY922 treatment led to induction of HSP70, a surrogate marker for inhibition of HSP90 function, but did not influence the protein level of HSP90 itself. HSP90 and its co-chaperones modulate tumor cell apoptosis, and much of their activity seems to be mediated through effects on the PI3K/Akt pathway and NF-κB function. Suppression of HSP90 function by AUY922 decreases the level of Akt, resulting in a reduction of activated p-Akt. The IKK complex, composed of IKKα, IKKβ, and IKKγ, is a positive regulator of NF-κB. In general, a decrease in the IKK complex inhibits phosphorylation of IκBα, resulting in its increased level. In the present study, AUY922 treatment decreased expression of the IKK complex in all tested cell lines. Among the apoptosis-related proteins examined, we found a decrease in survivin. Overall, we found similar changes in HSP90 client proteins regardless of the presence of wild-type or mutant p53 (Fig. 5).

Bottom Line: AUY922 caused strong upregulation of HSP70, a surrogate marker of HSP90 inhibition, and a dose-dependent decrease in HSP90 client proteins associated with cell survival, proliferation, and cell cycle in the G1 phase, including phospho-Akt, Akt, IKKα, IKKβ, IKKγ, Cdk4, Cdk6, and survivin.In fact, SGI-1776, a pan-PIM kinase inhibitor, successfully inhibited the growth of primary ATL cells as well as ATL-related cell lines.Our findings suggest that AUY922 is an effective therapeutic agent for ATL, and PIM kinases may be a novel therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Department of Hematology, Sasebo City General Hospital, Sasebo, Japan; Atomic Bomb Disease and Hibakusha Medicine Unit, Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

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Related in: MedlinePlus