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Published on: September 3, 2013
Prostate-specific antitumor activity by probasin promoter-directed p202 expression
Yong Wen1, Dipak Giri, Duen-Hwa Yan
1Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
p202, an interferon (IFN) inducible protein, arrests cell cycle at G1 phase leading to cell growth retardation. We previously showed that ectopic expression of p202 in human prostate cancer cells renders growth inhibition and suppression of transformation phenotype in vitro. In this report, we showed that prostate cancer cells with stable expression of p202 were less tumorigenic than the parental cells. The antitumor activity of p202 was further demonstrated by an ex vivo treatment of prostate cancer cells with p202 expression vector that showed significant tumor suppression in mouse xenograft model. Importantly, to achieve a prostate-specific antitumor effect by p202, we employed a prostate-specific probasin (ARR2PB) gene promoter to direct p202 expression (ARR2PB-p202) in an androgen receptor (AR)-positive manner. The ARR2PB-p202/liposome complex was systemically administered into mice bearing orthotopic AR-positive prostate tumors. We showed that parenteral administration of an ARR2PB-p202/liposome preparation led to prostate-specific p202 expression and tumor suppression in orthotopic prostate cancer xenograft model. Furthermore, with DNA array technique, we showed that the expression of p202 was accompanied by downregulation of G2/M phase cell-cycle regulators, cyclin B, and p55cdc. Together, our results suggest that p202 suppresses prostate tumor growth, and that a prostate-specific antitumor effect can be achieved by systemic administration of liposome-mediated delivery of ARR2PB-p202.
Insights
Interferon-inducible protein p202 inhibits prostate cancer growth by arresting the cell cycle. Systemic delivery of p202 using a prostate-specific promoter suppressed tumor growth in mice.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- p202 is an interferon-inducible protein that inhibits cell cycle progression.
- Previous studies demonstrated p202's in vitro anti-prostate cancer effects.
- Prostate cancer cells expressing p202 exhibit reduced tumorigenicity and transformation potential.
Purpose of the Study:
- To evaluate the in vivo antitumor activity of p202 in prostate cancer.
- To develop a prostate-specific gene therapy approach for prostate cancer using p202.
- To investigate the molecular mechanisms underlying p202-mediated tumor suppression.
Main Methods:
- Stable expression of p202 in human prostate cancer cells.
- In vivo studies using mouse xenograft models (ex vivo and orthotopic).
- Development and systemic administration of a liposome-mediated gene delivery system (ARR2PB-p202).
- DNA microarray analysis to identify downstream molecular targets.
Main Results:
- Prostate cancer cells with stable p202 expression showed reduced tumorigenicity.
- Systemic administration of ARR2PB-p202/liposome complex resulted in prostate-specific p202 expression and significant tumor suppression in orthotopic models.
- p202 expression correlated with the downregulation of G2/M cell-cycle regulators, including cyclin B and p55cdc.
Conclusions:
- p202 effectively suppresses prostate tumor growth.
- Liposome-mediated, prostate-specific delivery of ARR2PB-p202 offers a potential therapeutic strategy for prostate cancer.
- p202 exerts its antitumor effects partly by downregulating key cell-cycle regulators.
