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Survival-signaling pathway as a promising target for cancer chemotherapy
1Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, 113-0032, Tokyo, Japan. nfujita@iam.u-tokyo.ac.jp
Abstract:
The serine/threonine kinase AKT, also known as PKB or RAC-PK, is a key molecule for protecting cells from undergoing apoptosis. Several studies have suggested that the AKT-mediated survival-signaling pathway is an attractive target for cancer chemotherapy: (1) the AKT pathway is relatively inactive in resting cells; (2) amplification of the AKT gene occurs in some tumors; (3) loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome 10) is common in tumors and its loss constitutively activates AKT; (4) AKT is activated at the cancer invasion front. To clarify which drugs exhibit their cytotoxicity by inhibiting the AKT pathway, we screened anticancer drugs that could downregulate phospho-AKT levels and AKT kinase activity. We found that UCN-01 (7-hydroxystaurosporine), heat-shock protein 90 (HSP90) inhibitors, and topotecan (10-hydroxy-9-dimethylaminomethyl-(S)-camptothecin) possessed the ability to interfere with the AKT pathway. UCN-01 directly suppressed upstream AKT kinase 3-phosphoinositide-dependent protein kinase-1 (PDK1) (IC(50) <33 nM) both in vitro and in tumor xenografts. HSP90 inhibitors and topotecan suppressed AKT activity via indirectly downregulating PDK1 and phosphatidylinositide-3-OH kinase activities. Transfection of the constitutively active AKT complementary DNA into cells attenuated the cytotoxic effects of the drugs, indicating that inhibition of the AKT pathway plays an important role in exerting their cytotoxic effects. These results strongly suggest that the AKT-mediated survival-signaling pathway is a promising and attractive target for cancer chemotherapy.
Insights
Several anticancer drugs, including UCN-01 and HSP90 inhibitors, target the AKT pathway to induce cancer cell death. This pathway is crucial for cell survival and is often dysregulated in tumors, making it a promising target for chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The serine/threonine kinase AKT (also known as PKB or RAC-PK) is a critical regulator of cell survival, inhibiting apoptosis.
- The AKT-mediated survival pathway is a potential target for cancer chemotherapy due to its role in cancer progression, including gene amplification, loss of PTEN tumor suppressor, and activation at invasion fronts.
Purpose of the Study:
- To identify anticancer drugs that inhibit the AKT pathway by downregulating phospho-AKT levels and AKT kinase activity.
- To elucidate the mechanisms by which identified drugs interfere with AKT signaling.
Main Methods:
- Screening of anticancer drugs for their ability to inhibit AKT pathway activity.
- In vitro and in vivo assays using tumor xenografts to assess drug efficacy and mechanism of action.
- Transfection experiments with constitutively active AKT cDNA to confirm the role of AKT inhibition in drug-induced cytotoxicity.
Main Results:
- UCN-01 directly inhibited AKT kinase 3-phosphoinositide-dependent protein kinase-1 (PDK1) with high potency (IC50 <33 nM).
- Heat-shock protein 90 (HSP90) inhibitors and topotecan indirectly suppressed AKT activity by downregulating PDK1 and phosphatidylinositide-3-OH kinase.
- Inhibition of the AKT pathway was confirmed to be essential for the cytotoxic effects of these drugs, as evidenced by attenuated cytotoxicity in cells expressing active AKT.
Conclusions:
- UCN-01, HSP90 inhibitors, and topotecan demonstrate potential as AKT-targeting cancer therapeutics.
- The AKT-mediated survival pathway is a validated and promising target for developing novel cancer chemotherapy strategies.