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The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells.

Mandal M, Kim S, Younes MN, Jasser SA, El-Naggar AK, Mills GB, Myers JN - Br. J. Cancer (2005)

Bottom Line: Akt appears to be a key central node in this pathway and thus is an attractive target for targeted molecular therapy.KP372-1 blocked signalling downstream of Akt in thyroid tumour cells, leading to inhibition of cell proliferation and increased apoptosis.As thyroid cancer consistently expresses phosphorylated Akt and KP372-1 effectively blocks Akt signalling, further preclinical evaluation of this compound for treatment of thyroid cancer is warranted.

View Article: PubMed Central - PubMed

Affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

ABSTRACT
The phosphatidylinositol 3' kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome ten/Akt pathway, which is a critical regulator of cell proliferation and survival, is mutated or activated in a wide variety of cancers. Akt appears to be a key central node in this pathway and thus is an attractive target for targeted molecular therapy. We demonstrated that Akt is highly phosphorylated in thyroid cancer cell lines and human thyroid cancer specimens, and hypothesised that KP372-1, an Akt inhibitor, would block signalling through the PI3K pathway and inhibit cell proliferation while inducing apoptosis of thyroid cancer cells. KP372-1 blocked signalling downstream of Akt in thyroid tumour cells, leading to inhibition of cell proliferation and increased apoptosis. As thyroid cancer consistently expresses phosphorylated Akt and KP372-1 effectively blocks Akt signalling, further preclinical evaluation of this compound for treatment of thyroid cancer is warranted.

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Related in: MedlinePlus

KP372-1 inhibits Akt phosphorylation and some of the downstream signalling molecules as well as Akt kinase activity. (A) NPA187 and WRO cells were treated with the IC50 concentrations of KP372-1 (30–60 nM, respectively) for 4 h in RPMI medium without serum. Equal amounts of protein were resolved by SDS–polyacrylamide gel electrophoresis and immunoblotted with different antibodies as indicated. (B) KP372-1 inhibits Akt kinase activity. Different thyroid cancer cells were treated with KP372-1 for 2 h, cell lysates were prepared, and Akt was immunoprecipitated and analysed for Akt-Ser473 and Akt kinase activity using an in vitro kinase assay with GSK-β as a substrate. Results shown are representative of three experiments.
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fig7: KP372-1 inhibits Akt phosphorylation and some of the downstream signalling molecules as well as Akt kinase activity. (A) NPA187 and WRO cells were treated with the IC50 concentrations of KP372-1 (30–60 nM, respectively) for 4 h in RPMI medium without serum. Equal amounts of protein were resolved by SDS–polyacrylamide gel electrophoresis and immunoblotted with different antibodies as indicated. (B) KP372-1 inhibits Akt kinase activity. Different thyroid cancer cells were treated with KP372-1 for 2 h, cell lysates were prepared, and Akt was immunoprecipitated and analysed for Akt-Ser473 and Akt kinase activity using an in vitro kinase assay with GSK-β as a substrate. Results shown are representative of three experiments.

Mentions: We next determined the effect of KP372-1 on the phosphorylation of AKT (Ser473) and on downstream targets of Akt, including p-mTOR and p-S6 ribosomal protein (Ser240/244), and MAPK. We treated NPA187 and WRO cells with KP372-1 at their respective IC50 for 4 h and analysed the cell lysates with the specific antibodies indicated in Figure 7A. In the case of NPA187 and WRO, phosphorylation of Akt and S6 ribosomal protein was downregulated by treatment with KP372-1. However, the phosphorylation of mTOR and MAPK was not changed by treatment with KP372-1. Akt kinase activity was also downregulated by KP372-1 in multiple thyroid cancer cell lines, as tested by an in vitro kinase assay using GSK-β as substrate (Figure 7B).


The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells.

Mandal M, Kim S, Younes MN, Jasser SA, El-Naggar AK, Mills GB, Myers JN - Br. J. Cancer (2005)

KP372-1 inhibits Akt phosphorylation and some of the downstream signalling molecules as well as Akt kinase activity. (A) NPA187 and WRO cells were treated with the IC50 concentrations of KP372-1 (30–60 nM, respectively) for 4 h in RPMI medium without serum. Equal amounts of protein were resolved by SDS–polyacrylamide gel electrophoresis and immunoblotted with different antibodies as indicated. (B) KP372-1 inhibits Akt kinase activity. Different thyroid cancer cells were treated with KP372-1 for 2 h, cell lysates were prepared, and Akt was immunoprecipitated and analysed for Akt-Ser473 and Akt kinase activity using an in vitro kinase assay with GSK-β as a substrate. Results shown are representative of three experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361761&req=5

fig7: KP372-1 inhibits Akt phosphorylation and some of the downstream signalling molecules as well as Akt kinase activity. (A) NPA187 and WRO cells were treated with the IC50 concentrations of KP372-1 (30–60 nM, respectively) for 4 h in RPMI medium without serum. Equal amounts of protein were resolved by SDS–polyacrylamide gel electrophoresis and immunoblotted with different antibodies as indicated. (B) KP372-1 inhibits Akt kinase activity. Different thyroid cancer cells were treated with KP372-1 for 2 h, cell lysates were prepared, and Akt was immunoprecipitated and analysed for Akt-Ser473 and Akt kinase activity using an in vitro kinase assay with GSK-β as a substrate. Results shown are representative of three experiments.
Mentions: We next determined the effect of KP372-1 on the phosphorylation of AKT (Ser473) and on downstream targets of Akt, including p-mTOR and p-S6 ribosomal protein (Ser240/244), and MAPK. We treated NPA187 and WRO cells with KP372-1 at their respective IC50 for 4 h and analysed the cell lysates with the specific antibodies indicated in Figure 7A. In the case of NPA187 and WRO, phosphorylation of Akt and S6 ribosomal protein was downregulated by treatment with KP372-1. However, the phosphorylation of mTOR and MAPK was not changed by treatment with KP372-1. Akt kinase activity was also downregulated by KP372-1 in multiple thyroid cancer cell lines, as tested by an in vitro kinase assay using GSK-β as substrate (Figure 7B).

Bottom Line: Akt appears to be a key central node in this pathway and thus is an attractive target for targeted molecular therapy.KP372-1 blocked signalling downstream of Akt in thyroid tumour cells, leading to inhibition of cell proliferation and increased apoptosis.As thyroid cancer consistently expresses phosphorylated Akt and KP372-1 effectively blocks Akt signalling, further preclinical evaluation of this compound for treatment of thyroid cancer is warranted.

View Article: PubMed Central - PubMed

Affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

ABSTRACT
The phosphatidylinositol 3' kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome ten/Akt pathway, which is a critical regulator of cell proliferation and survival, is mutated or activated in a wide variety of cancers. Akt appears to be a key central node in this pathway and thus is an attractive target for targeted molecular therapy. We demonstrated that Akt is highly phosphorylated in thyroid cancer cell lines and human thyroid cancer specimens, and hypothesised that KP372-1, an Akt inhibitor, would block signalling through the PI3K pathway and inhibit cell proliferation while inducing apoptosis of thyroid cancer cells. KP372-1 blocked signalling downstream of Akt in thyroid tumour cells, leading to inhibition of cell proliferation and increased apoptosis. As thyroid cancer consistently expresses phosphorylated Akt and KP372-1 effectively blocks Akt signalling, further preclinical evaluation of this compound for treatment of thyroid cancer is warranted.

Show MeSH
Related in: MedlinePlus