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Tumour suppressive function and modulation of programmed cell death 4 (PDCD4) in ovarian cancer
Na Wei1, Stephanie S Liu, Karen K L Chan
1Department of Obstetrics & Gynaecology, Queen Mary Hospital, the University of Hong Kong, Hong Kong, Hong Kong.
Background:
Programmed cell death 4 (PDCD4), originally identified as the neoplastic transformation inhibitor, was attenuated in various cancer types. Our previous study demonstrated a continuous down-regulation of PDCD4 expression in the sequence of normal-borderline-malignant ovarian tissue samples and a significant correlation of PDCD4 expression with disease-free survival. The objective of the current study was to further investigate the function and modulation of PDCD4 in ovarian cancer cells.
Principal Findings:
We demonstrated that ectopic PDCD4 expression significantly inhibited cell proliferation by inducing cell cycle arrest at G(1) stage and up-regulation of cell cycle inhibitors of p27 and p21. Cell migration and invasion were also inhibited by PDCD4. PDCD4 over-expressing cells exhibited elevated phosphatase and tensin homolog (PTEN) and inhibited protein kinase B (p-Akt). In addition, the expression of PDCD4 was up-regulated and it was exported to the cytoplasm upon serum withdrawal treatment, but it was rapidly depleted via proteasomal degradation upon serum re-administration. Treatment of a phosphoinositide 3-kinase (PI3K) inhibitor prevented the degradation of PDCD4, indicating the involvement of PI3K-Akt pathway in the modulation of PDCD4.
Conclusion:
PDCD4 may play a critical function in arresting cell cycle progression at key checkpoint, thus inhibiting cell proliferation, as well as suppressing tumour metastasis. The PI3K-Akt pathway was implied to be involved in the regulation of PDCD4 degradation in ovarian cancer cells. In response to the stress condition, endogenous PDCD4 was able to shuttle between cell compartments to perform its diverted functions.
Insights
Programmed cell death 4 (PDCD4) inhibits ovarian cancer cell proliferation and metastasis by arresting the cell cycle. Its degradation is regulated by the PI3K-Akt pathway, suggesting therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Programmed cell death 4 (PDCD4) is a neoplastic transformation inhibitor with reduced expression in various cancers.
- PDCD4 expression is progressively down-regulated in normal-to-malignant ovarian tissues, correlating with reduced disease-free survival.
- Investigating PDCD4's function and regulation in ovarian cancer is crucial.
Purpose of the Study:
- To elucidate the functional role of PDCD4 in ovarian cancer cells.
- To understand the regulatory mechanisms governing PDCD4 expression and activity.
Main Methods:
- Ectopic expression of PDCD4 in ovarian cancer cells.
- Cell cycle analysis (G1 arrest, p27, p21).
- Cell migration and invasion assays.
- Western blotting for PTEN, p-Akt.
- Analysis of PDCD4 expression and localization under serum withdrawal/re-administration.
- Treatment with PI3K inhibitor.
Main Results:
- Ectopic PDCD4 expression inhibited ovarian cancer cell proliferation, induced G1 cell cycle arrest, and increased p27 and p21.
- PDCD4 suppressed cell migration and invasion, elevated PTEN, and inhibited Akt phosphorylation.
- PDCD4 expression increased and localized to the cytoplasm upon serum withdrawal, but was degraded via proteasomes upon serum re-administration.
- PI3K inhibition prevented PDCD4 degradation, implicating the PI3K-Akt pathway.
Conclusions:
- PDCD4 is a critical inhibitor of cell cycle progression and tumor metastasis in ovarian cancer.
- The PI3K-Akt pathway regulates PDCD4 degradation in ovarian cancer cells.
- Endogenous PDCD4 exhibits dynamic compartmental shuttling in response to cellular stress, performing diverse functions.
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