Tetrandrine triggers an alternative autophagy in DU145 cells
Wei Qiu1, Ai-Li Zhang2, Ye Tian1
1Department of Urology, Beijing Friendship Hospital, Capital Medical University, Xicheng, Beijing 100050, P.R. China.
Abstract:
Tetrandrine (Tet), a potent lysosomal inhibitor, blocks autophagic flux and induces cancer cell death. Previously, the present authors identified the prostate cancer cell line DU145 to exhibit high sensitivity towards Tet in 11 cancer cell lines. In the present study, autophagy in Tet-treated DU145 cells was investigated. Similar to other cell lines, such as PC-3 and 786-O cells, Tet neutralized the acidity of lysosome and blocked autophagy in DU145 cells. However, Tet failed to induce microtubule-associated protein 1 light chain 3 (LC3) conversion in DU145 cells. By contrast, it was observed by transmission electron microscopy that Tet induced an accumulation of autophagosomes in the cytoplasm. These contrasting results indicated that Tet triggered an LC3-independent autophagy in DU145 cells. Alkalizing lysosome with chloroquine enhanced Tet-induced cell death. The results of the present study indicated that detection of autophagy in tumor cells may assist in selecting lysosome inhibitors for chemotherapy treatment in prostate cancer.
Insights
Tetrandrine blocks lysosome function and induces cancer cell death. In prostate cancer DU145 cells, it triggers autophagy independently of LC3, enhancing cell death when combined with chloroquine.
Area of Science:
- Cell Biology
- Cancer Research
- Pharmacology
Background:
- Tetrandrine (Tet) is a lysosomal inhibitor known to block autophagic flux and induce cancer cell death.
- Previous studies identified DU145 prostate cancer cells as highly sensitive to Tet.
- Understanding Tet's mechanism in sensitive cell lines is crucial for targeted cancer therapy.
Purpose of the Study:
- To investigate the specific effects of Tetrandrine on autophagy in DU145 prostate cancer cells.
- To elucidate the mechanism of Tet-induced cell death in this specific cancer cell line.
- To explore the potential of combining Tet with other agents to enhance therapeutic efficacy.
Main Methods:
- Treatment of DU145 cells with Tetrandrine.
- Analysis of lysosomal acidity and autophagic flux.
- Assessment of microtubule-associated protein 1 light chain 3 (LC3) conversion.
- Transmission electron microscopy to observe autophagosome accumulation.
- Combination treatment with chloroquine to evaluate synergistic effects on cell death.
Main Results:
- Tetrandrine neutralized lysosomal acidity and blocked autophagic flux in DU145 cells, similar to other cancer cell lines.
- Contrary to expectations, Tetrandrine did not induce LC3 conversion in DU145 cells.
- Transmission electron microscopy revealed an accumulation of autophagosomes, indicating LC3-independent autophagy.
- Co-administration of chloroquine potentiated Tetrandrine-induced cancer cell death.
Conclusions:
- Tetrandrine induces an LC3-independent autophagic response in DU145 prostate cancer cells.
- Lysosomal inhibition by Tetrandrine enhances cancer cell death, particularly when combined with agents that further disrupt lysosomal function.
- Monitoring autophagy in tumors may aid in selecting appropriate lysosomal inhibitors for prostate cancer chemotherapy.
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