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Inhibition of constitutively active Jak-Stat pathway suppresses cell growth of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells.

Tomita M, Kawakami H, Uchihara JN, Okudaira T, Masuda M, Matsuda T, Tanaka Y, Ohshiro K, Mori N - Retrovirology (2006)

Bottom Line: Using AG490, a Jak-specific inhibitor, we demonstrated that the activation of Stat3 and Stat5 was mediated by the constitutive phosphorylation of Jak proteins.AG490 inhibited the growth of HTLV-1-infected T-cell lines and primary ATL cells by inducing G1 cell-cycle arrest mediated by altering the expression of cyclin D2, Cdk4, p53, p21, Pim-1 and c-Myc, and by apoptosis mediated by the reduced expression of c-IAP2, XIAP, survivin and Bcl-2.Inhibition of this pathway may provide a new approach for the treatment of ATL.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. mtomita@med.u-ryukyu.ac.jp

ABSTRACT

Background: Human T-cell leukemia virus type 1 (HTLV-1), the etiologic agent for adult T-cell leukemia (ATL), induces cytokine-independent proliferation of T-cells, associated with the acquisition of constitutive activation of Janus kinases (Jak) and signal transducers and activators of transcription (Stat) proteins. Our purposes in this study were to determine whether activation of Jak-Stat pathway is responsible for the proliferation and survival of ATL cells, and to explore mechanisms by which inhibition of Jak-Stat pathway kills ATL cells.

Results: Constitutive activation of Stat3 and Stat5 was observed in HTLV-1-infected T-cell lines and primary ATL cells, but not in HTLV-1-negative T-cell lines. Using AG490, a Jak-specific inhibitor, we demonstrated that the activation of Stat3 and Stat5 was mediated by the constitutive phosphorylation of Jak proteins. AG490 inhibited the growth of HTLV-1-infected T-cell lines and primary ATL cells by inducing G1 cell-cycle arrest mediated by altering the expression of cyclin D2, Cdk4, p53, p21, Pim-1 and c-Myc, and by apoptosis mediated by the reduced expression of c-IAP2, XIAP, survivin and Bcl-2. Importantly, AG490 did not inhibit the growth of normal peripheral blood mononuclear cells.

Conclusion: Our results indicate that activation of Jak-Stat pathway is responsible for the proliferation and survival of ATL cells. Inhibition of this pathway may provide a new approach for the treatment of ATL.

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Related in: MedlinePlus

HTLV-1 Tax does not involve in phosphorylation of Stat3 and Stat5. Cell lysates were prepared from CdCl2-treated JPX-9 cells at the indicated time points (lanes 1–7) and untreated MT-2 cells (lane 8: as a positive control). The expression of phospho-Stat3, Stat3, phospho-Stat5, Stat5 and Tax (arrow) was analyzed by Western blot. Actin expression served as a loading control.
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Figure 2: HTLV-1 Tax does not involve in phosphorylation of Stat3 and Stat5. Cell lysates were prepared from CdCl2-treated JPX-9 cells at the indicated time points (lanes 1–7) and untreated MT-2 cells (lane 8: as a positive control). The expression of phospho-Stat3, Stat3, phospho-Stat5, Stat5 and Tax (arrow) was analyzed by Western blot. Actin expression served as a loading control.

Mentions: We next examined whether HTLV-1 Tax protein alters the phosphorylation status of Stat3 and Stat5. Tax-inducible T-cell line, JPX-9 expressed Tax 10 h after addition of CdCl2 and the expression persisted until 72 h after treatment (Figure 2, second panel from the bottom, lanes 4–7). Although Stat3 and Stat5 were consistently expressed in JPX-9 cells even after CdCl2 treatment, phosphorylated Stat3 and Stat5 were not detected in these cells (Figure 2, first and third panels). These results suggest that Tax is not involved in the induction of Stat3 and Stat5 phosphorylation in T-cells.


Inhibition of constitutively active Jak-Stat pathway suppresses cell growth of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells.

Tomita M, Kawakami H, Uchihara JN, Okudaira T, Masuda M, Matsuda T, Tanaka Y, Ohshiro K, Mori N - Retrovirology (2006)

HTLV-1 Tax does not involve in phosphorylation of Stat3 and Stat5. Cell lysates were prepared from CdCl2-treated JPX-9 cells at the indicated time points (lanes 1–7) and untreated MT-2 cells (lane 8: as a positive control). The expression of phospho-Stat3, Stat3, phospho-Stat5, Stat5 and Tax (arrow) was analyzed by Western blot. Actin expression served as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1483830&req=5

Figure 2: HTLV-1 Tax does not involve in phosphorylation of Stat3 and Stat5. Cell lysates were prepared from CdCl2-treated JPX-9 cells at the indicated time points (lanes 1–7) and untreated MT-2 cells (lane 8: as a positive control). The expression of phospho-Stat3, Stat3, phospho-Stat5, Stat5 and Tax (arrow) was analyzed by Western blot. Actin expression served as a loading control.
Mentions: We next examined whether HTLV-1 Tax protein alters the phosphorylation status of Stat3 and Stat5. Tax-inducible T-cell line, JPX-9 expressed Tax 10 h after addition of CdCl2 and the expression persisted until 72 h after treatment (Figure 2, second panel from the bottom, lanes 4–7). Although Stat3 and Stat5 were consistently expressed in JPX-9 cells even after CdCl2 treatment, phosphorylated Stat3 and Stat5 were not detected in these cells (Figure 2, first and third panels). These results suggest that Tax is not involved in the induction of Stat3 and Stat5 phosphorylation in T-cells.

Bottom Line: Using AG490, a Jak-specific inhibitor, we demonstrated that the activation of Stat3 and Stat5 was mediated by the constitutive phosphorylation of Jak proteins.AG490 inhibited the growth of HTLV-1-infected T-cell lines and primary ATL cells by inducing G1 cell-cycle arrest mediated by altering the expression of cyclin D2, Cdk4, p53, p21, Pim-1 and c-Myc, and by apoptosis mediated by the reduced expression of c-IAP2, XIAP, survivin and Bcl-2.Inhibition of this pathway may provide a new approach for the treatment of ATL.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. mtomita@med.u-ryukyu.ac.jp

ABSTRACT

Background: Human T-cell leukemia virus type 1 (HTLV-1), the etiologic agent for adult T-cell leukemia (ATL), induces cytokine-independent proliferation of T-cells, associated with the acquisition of constitutive activation of Janus kinases (Jak) and signal transducers and activators of transcription (Stat) proteins. Our purposes in this study were to determine whether activation of Jak-Stat pathway is responsible for the proliferation and survival of ATL cells, and to explore mechanisms by which inhibition of Jak-Stat pathway kills ATL cells.

Results: Constitutive activation of Stat3 and Stat5 was observed in HTLV-1-infected T-cell lines and primary ATL cells, but not in HTLV-1-negative T-cell lines. Using AG490, a Jak-specific inhibitor, we demonstrated that the activation of Stat3 and Stat5 was mediated by the constitutive phosphorylation of Jak proteins. AG490 inhibited the growth of HTLV-1-infected T-cell lines and primary ATL cells by inducing G1 cell-cycle arrest mediated by altering the expression of cyclin D2, Cdk4, p53, p21, Pim-1 and c-Myc, and by apoptosis mediated by the reduced expression of c-IAP2, XIAP, survivin and Bcl-2. Importantly, AG490 did not inhibit the growth of normal peripheral blood mononuclear cells.

Conclusion: Our results indicate that activation of Jak-Stat pathway is responsible for the proliferation and survival of ATL cells. Inhibition of this pathway may provide a new approach for the treatment of ATL.

Show MeSH
Related in: MedlinePlus