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Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis
1Department of Obstetrics and Gynecology, University of Michigan Comprehensive Cancer Center, Ann Arbor 48109, USA.
Abstract:
The AKT oncogenes are amplified or AKT kinase activity is constitutively elevated in several types of human malignancy. We sought to determine whether AKT might play a role in the development of resistance to apoptosis induced by chemotherapy. We showed that ovarian cancer cells either overexpressing constitutively active Akt/AKT1 or containing AKT2 gene amplification were highly resistant to paclitaxel than cancer cells express low AKT levels. The Akt/AKT1 clones also contained higher levels of phospho-Bad protein than parental cells. Further, the complexes between the endogenous proapoptotic protein, Bad, and the anti-apoptotic protein, BC1-XL were undetectable in Akt/AKT1 clones. These results suggest that Akt/AKT1 expressed in these clones can phosphorylate Bad and prevent it from binding to Bcl-XL. Furthermore, overexpression of Akt/AKT1 can inhibit the release of cytochrome c induced by paclitaxel. Therefore, our findings provide evidence that aberrant expression or activation of AKT in cancer cells may confer resistance to paclitaxel.
Insights
Aberrant AKT oncogene activation in cancer cells promotes resistance to paclitaxel chemotherapy. This occurs by AKT phosphorylating Bad, preventing its interaction with Bcl-XL, and inhibiting cytochrome c release, thus conferring chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The AKT oncogenes are frequently amplified or exhibit elevated kinase activity in human malignancies.
- Chemotherapy resistance, particularly to paclitaxel, is a significant challenge in cancer treatment.
- The role of AKT in mediating resistance to apoptosis induced by chemotherapy requires further elucidation.
Purpose of the Study:
- To investigate the potential role of AKT in the development of resistance to chemotherapy-induced apoptosis.
- To determine if AKT activation influences sensitivity to paclitaxel in ovarian cancer cells.
Main Methods:
- Ovarian cancer cell lines with varying AKT1/AKT2 expression levels were utilized.
- Analysis of paclitaxel resistance, phospho-Bad protein levels, and Bad/Bcl-XL complex formation.
- Assessment of cytochrome c release following paclitaxel treatment in relation to AKT activity.
Main Results:
- Ovarian cancer cells overexpressing constitutively active Akt/AKT1 or with AKT2 gene amplification exhibited heightened resistance to paclitaxel.
- Elevated levels of phospho-Bad were observed in Akt/AKT1-expressing cells.
- Paclitaxel treatment did not induce cytochrome c release in Akt/AKT1-overexpressing cells, suggesting inhibition of apoptosis.
Conclusions:
- Aberrant AKT expression or activation in cancer cells confers resistance to paclitaxel.
- AKT-mediated phosphorylation of Bad prevents its interaction with Bcl-XL, thereby inhibiting apoptosis.
- These findings highlight AKT as a potential therapeutic target for overcoming paclitaxel resistance in cancer.