Telomerase suppression initiates PML-dependent p53 activation to inhibit bladder cancer cell growth.

Abstract

Most human cancer cells maintain telomere to immortalization through telomerase activity. Inhibition of telomerase activity is a powerful strategy for cancer therapy; however, the potential molecular signals following telomerase suppression are still not clear. Promyelocytic leukemia protein (PML) is an essential component of PML nuclear bodies and a tumor suppressor in bladder cancer. In this study, using mutant human telomerase reverse transcriptase (hTERT) or shRNA to inhibit telomerase activity, we found telomerase suppression increased the expression of PML and resulted in its translocation to the nucleus in bladder cancer T24 cells. Additionally, we found that p53 was recruited into nucleus and colocalized with PML after telomerase suppression. Subsequently, there was a decrease in cell growth in vitro and in vivo and an increase in cell cycle arrest and apoptosis. Furthermore, we showed here that PML is indispensable for p53 nuclear translocation and p21 induction after telomerase inhibition. Therefore, our data indicate that suppression of telomerase could activate the PML-dependent p53 signaling pathway and inhibit bladder cancer cell growth, and also provide new insight into the potential crosstalk between PML and hTERT in bladder cancer cells.

• Authors: Yan Xue, Lei Li, Dong Zhang, Kaijie Wu, Peng Guo, Jin Zeng, Xinyang Wang, Dalin He
• Journal: Oncology reports (Oncol Rep) Vol. 24 Issue 6 Pg. 1551-9 (Dec 2010) ISSN: 1791-2431 [Electronic] Greece
• PMID: 21042751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nuclear Proteins
• Promyelocytic Leukemia Protein
• RNA, Small Interfering
• Transcription Factors
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• PML protein, human
• TERT protein, human
• Telomerase

Topics

• Animals
• Carcinoma (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Mice
• Mice, Nude
• Nuclear Proteins (metabolism, physiology)
• Promyelocytic Leukemia Protein
• Protein Transport (drug effects)
• RNA, Small Interfering (pharmacology)
• Telomerase (antagonists & inhibitors, genetics, metabolism)
• Transcription Factors (metabolism, physiology)
• Transfection
• Tumor Burden (drug effects)
• Tumor Suppressor Protein p53 (metabolism)
• Tumor Suppressor Proteins (metabolism, physiology)
• Urinary Bladder Neoplasms (genetics, metabolism, pathology)
• Xenograft Model Antitumor Assays