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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 90 inhibitor AUY922 on Moloney murine leukemia virus (PIM) kinases in adult T-cell leukemia–lymphoma. Western blot analysis revealed that AUY922 induced downregulation of PIM-1, -2, and -3 in adult T-cell leukemia–lymphoma-related cell lines.
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fig06: Effects of heat shock protein 90 inhibitor AUY922 on Moloney murine leukemia virus (PIM) kinases in adult T-cell leukemia–lymphoma. Western blot analysis revealed that AUY922 induced downregulation of PIM-1, -2, and -3 in adult T-cell leukemia–lymphoma-related cell lines.

Mentions: To determine which molecules play important roles in AUY922-induced ATL-cell death, gene expression profiling was carried out using DNA microarray analysis. Among genes with changes in average expression of at least 1.5-fold (log2 ratio) in either direction in the four tested cell lines, we selected those with known functions related to apoptosis, cell cycle, and cell proliferation. Our results showed upregulation of HSP70 in those cells, which was consistent with the results of our WB analysis, and we also noted upregulation of HSP90, although the protein level of HSP90 was not changed. Interestingly, decreases in two of the PIM kinases, PIM-1 and -3, were commonly found (Table 1). PIM has multiple cellular functions related to cell survival, proliferation, differentiation, apoptosis, and tumorigenesis, and its expression is also correlated with poor prognosis in most hematopoietic malignancies, although its role in ATL remains unclear. Therefore, to investigate this, we examined the protein expression levels of PIM kinases using WB in ATL-related cell lines treated by AUY922. Although the protein levels of PIM kinases varied in each of the cell lines when untreated, the protein expression levels of PIM-1, -2, and -3 were universally decreased in all treated cell lines (Fig. 6).


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 90 inhibitor AUY922 on Moloney murine leukemia virus (PIM) kinases in adult T-cell leukemia–lymphoma. Western blot analysis revealed that AUY922 induced downregulation of PIM-1, -2, and -3 in adult T-cell leukemia–lymphoma-related cell lines.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig06: Effects of heat shock protein 90 inhibitor AUY922 on Moloney murine leukemia virus (PIM) kinases in adult T-cell leukemia–lymphoma. Western blot analysis revealed that AUY922 induced downregulation of PIM-1, -2, and -3 in adult T-cell leukemia–lymphoma-related cell lines.
Mentions: To determine which molecules play important roles in AUY922-induced ATL-cell death, gene expression profiling was carried out using DNA microarray analysis. Among genes with changes in average expression of at least 1.5-fold (log2 ratio) in either direction in the four tested cell lines, we selected those with known functions related to apoptosis, cell cycle, and cell proliferation. Our results showed upregulation of HSP70 in those cells, which was consistent with the results of our WB analysis, and we also noted upregulation of HSP90, although the protein level of HSP90 was not changed. Interestingly, decreases in two of the PIM kinases, PIM-1 and -3, were commonly found (Table 1). PIM has multiple cellular functions related to cell survival, proliferation, differentiation, apoptosis, and tumorigenesis, and its expression is also correlated with poor prognosis in most hematopoietic malignancies, although its role in ATL remains unclear. Therefore, to investigate this, we examined the protein expression levels of PIM kinases using WB in ATL-related cell lines treated by AUY922. Although the protein levels of PIM kinases varied in each of the cell lines when untreated, the protein expression levels of PIM-1, -2, and -3 were universally decreased in all treated cell lines (Fig. 6).

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.

Show MeSH
Related in: MedlinePlus