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Inhibition of protein kinase B/Akt. implications for cancer therapy
Michelle M Hill1, Brian A Hemmings
1Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058, Basel, Switzerland.
Abstract:
Protein kinase B (PKB, also called Akt) is an important regulator of cell proliferation and survival. Amplification of genes encoding PKB isoforms has been found in several types of human cancers. In addition, mutations in the phosphatase and tensin homolog deleted on chromosome ten (PTEN), one of the most frequently mutated tumor suppressor genes, results in elevated PKB activity. PKB has a wide range of cellular targets, and the oncogenicity of PKB arises from activation of both proliferative and anti-apoptotic signaling. Furthermore, PKB contributes to tumor progression by promoting cell invasiveness and angiogenesis. These observations establish PKB as an attractive target for cancer therapy. A cellular inhibitor of PKB, termed carboxyl-terminal modulator protein, reverts the phenotype of viral akt-transformed cells, suggesting that a specific PKB inhibitor will be useful in the treatment of tumors with elevated PKB activity. Since inhibition of PKB activity induces apoptosis in a range of mammalian cells, a PKB inhibitor may be effective, in combination with other anticancer drugs, for the treatment of tumors with other mutations.
Insights
Protein kinase B (PKB) is crucial for cell growth and survival, and its overactivity drives cancer. Inhibiting PKB shows promise as a targeted cancer therapy, potentially enhancing other treatments.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Protein kinase B (PKB), also known as Akt, is a key regulator of cell proliferation and survival.
- Elevated PKB activity is implicated in various human cancers due to gene amplification or PTEN mutations.
- PKB's role in promoting proliferation, inhibiting apoptosis, and driving tumor progression makes it a significant therapeutic target.
Purpose of the Study:
- To highlight Protein Kinase B (PKB) as a promising therapeutic target in cancer treatment.
- To underscore the role of PKB in oncogenesis and tumor progression.
- To suggest the potential of PKB inhibitors in cancer therapy, possibly in combination with other drugs.
Main Methods:
- Review of existing literature on PKB's role in cancer.
- Analysis of genetic alterations (gene amplification, PTEN mutations) leading to elevated PKB activity.
- Examination of PKB's cellular targets and signaling pathways involved in proliferation and apoptosis.
Main Results:
- PKB amplification and PTEN mutations frequently occur in human cancers, leading to increased PKB activity.
- PKB activation drives cancer by promoting cell proliferation and survival (anti-apoptotic signaling).
- PKB also contributes to tumor progression through enhanced invasiveness and angiogenesis.
Conclusions:
- PKB is an attractive molecular target for developing novel cancer therapies.
- Specific PKB inhibitors, like carboxyl-terminal modulator protein, can revert cancer cell phenotypes.
- PKB inhibitors may be effective in treating tumors with elevated PKB activity and could be used in combination therapies for various mutations.