Conditional PTEN-deficient Mice as a Prostate Cancer Chemoprevention Model

Koike, Hiroyuki; Nozawa, Masahiro; Velasco, Marco A. De; Kura, Yurie; Ando, Naomi; Fukushima, Emiko; Yamamoto, Yutaka; Hatanaka, Yuji; Yoshikawa, Kazuhiro; Nishio, Kazuto; Uemura, Hirotsugu

doi:10.7314/apjcp.2015.16.5.1827

Cited by 10 publications

(9 citation statements)

References 25 publications

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“…To investigate the function of PTEN, various knockout mice have been prepared and the effect of PTEN deficiency examined (9). The authors also established a conditional PTEN-deficient mouse model of prostate cancer driven by the PSA-Cre promoter and demonstrated its utility in various experimental settings (10)(11)(12)(13). To develop better treatment strategies requires a deeper understanding the cellular and molecular mechanisms of PTEN deficiency.…”

Section: Introductionmentioning

confidence: 99%

Generation of PTEN‑knockout (‑/‑) murine prostate cancer cells using the CRISPR/Cas9 system and comprehensive gene expression profiling

et al. 2018

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Phosphatase and tensin homolog (PTEN) deficiency is associated with development, progression, and metastasis of various cancers. However, changes in gene expression associated with PTEN deficiency have not been fully characterized. To explore genes with altered expression in PTEN‑deficient cells, the present study generated a PTEN‑knockout cell line (ΔPTEN) from a mouse prostate cancer‑derived cell line using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‑associated protein 9 (CRISPR/Cas9) gene editing system. Following transfection of the CRISPR/Cas9 construct, DNA sequencing was performed to identify deletion of the Pten locus and PTEN inactivation was verified by western blotting. The ΔPTEN cell line exhibited enhanced RAC‑alpha serine/threonine‑protein kinase phosphorylation and cyclin D1 expression. In addition, an increase in cell proliferation and colony formation was observed in the ΔPTEN cell line. Gene expression profiling experiments were analyzed with microarray and microRNA (miRNA) arrays. In the microarray analysis, 111 genes exhibited ≥10‑fold increased expression compared with the parent strain and mock cell line and 23 genes were downregulated. The only miRNA with increased expression of 10‑fold or more was mmu‑miR‑210‑3p. Genes with enhanced expression included genes involved in the development, progression, and metastasis of cancer such as Tet methylcytosine dioxygenase 1, twist family BHLH transcription factor 2, C‑fos‑induced growth factor and Wingless‑Type MMTV Integration Site Family, Member 3, and genes involved in immunosuppression such as Arginase 1. The results of the present study suggest that PTEN deficiency mobilizes a variety of genes critical for cancer cell survival and host immune evasion.

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Section: Introductionmentioning

confidence: 99%

Generation of PTEN‑knockout (‑/‑) murine prostate cancer cells using the CRISPR/Cas9 system and comprehensive gene expression profiling

et al. 2018

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“…Aberrant activation of AKT leads to tumorigenesis, drug resistance and metastasis. Therefore, AKT has become an important therapeutic target for various types of cancer, including prostate cancer (CaP) [4], [5], [6]. Despite advances in early detection and an improved understanding of the molecular mechanism of CaP, the mortality associated with CaP in the US remains high [7].…”

Section: Introductionmentioning

confidence: 99%

“…Conditional knockout GEMMs, in which tumor-associated genes are selectively inactivated in the cancer-bearing tissue of interest using Cre-LoxP recombination, are important tools for gaining mechanistic insights into cancer and for evaluating the efficacy of cancer therapeutics in clinically relevant models [10]. These GEMMs include a conditional phosphatase and tensin homologue ( PTEN) tumor suppressor gene-deficient GEMM of the prostate, which is actively being studied as a context-specific model for evaluating the chemoprevention of CaP [4], [5].…”

Section: Introductionmentioning

confidence: 99%

Withaferin A Inhibits Prostate Carcinogenesis in a PTEN-deficient Mouse Model of Prostate Cancer

et al. 2017

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We recently demonstrated that AKT activation plays a role in prostate cancer progression and inhibits the pro-apoptotic function of FOXO3a and Par-4. AKT inhibition and Par-4 induction suppressed prostate cancer progression in preclinical models. Here, we investigate the chemopreventive effect of the phytonutrient Withaferin A (WA) on AKT-driven prostate tumorigenesis in a Pten conditional knockout (Pten-KO) mouse model of prostate cancer. Oral WA treatment was carried out at two different doses (3 and 5 mg/kg) and compared to vehicle over 45 weeks. Oral administration of WA for 45 weeks effectively inhibited primary tumor growth in comparison to vehicle controls. Pathological analysis showed the complete absence of metastatic lesions in organs from WA-treated mice, whereas discrete metastasis to the lungs was observed in control tumors. Immunohistochemical analysis revealed the down-regulation of pAKT expression and epithelial-to-mesenchymal transition markers, such as β-catenin and N-cadherin, in WA-treated tumors in comparison to controls. This result corroborates our previous findings from both cell culture and xenograft models of prostate cancer. Our findings demonstrate that the daily administration of a phytonutrient that targets AKT activation provides a safe and effective treatment for prostate cancer in a mouse model with strong potential for translation to human disease.

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“…The findings from this study suggest that inhibiting androgen signaling is effective in preventing the proliferation of prostate cancer caused by PTEN dysfunction. It has also been suggested that androgen plays an important role at the early stages of prostate cancer development in this mouse model [27].…”

Section: Clinical Study and Basic Researchmentioning

confidence: 66%

“…Another study has evaluated whether chlormadinone has a more favorable effect on lipid and bone metabolism than that of bicalutamide (No.2; UMIN000018478). In terms of basic research, Koike et al [27] have reported on the effects of chlormadinone acetate on the development and progression of prostate cancer in their PTEN-deficient mouse model ( Table 1, No. 3).…”

Section: Clinical Study and Basic Researchmentioning

confidence: 99%

Reconsideration of Hormonal Therapy in the Era of Next‐ Generation Hormonal Therapy

Miyata¹,

Shida²,

Matsuo³

et al. 2016

Prostate Cancer - Leading-Edge Diagnostic Procedures and Treatments

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Hormonal therapy is a major and effective tool in the treatment of prostate cancer patients. This is especially true for patients in the advanced stages of disease. Unfortunately, almost all prostate cancer cells will develop into castration-resistant prostate cancer (CRPC) despite continued therapy and suppression of testosterone levels. Up until 5-6 years ago, there was little effective therapy for the treatment of CRPC patients. However, recently, a variety of methodologies and drugs such as cabazitaxel and sipuleucel-T have been approved globally for the treatment of CRPC. Two novel drugs, abiraterone acetate and enzartamide, have also become available as potential treatment options. However, the anticancer effects of these two drugs are not always satisfactory in terms of prolonging survival. These drugs are also associated with adverse events and are expensive when compared with the costs of previously used anticancer drugs. In this section, we pay particular attention to hormonal therapies that do not include the use of abiraterone acetate or enzartamide. We believe that a detailed understanding of the range of currently available hormonal therapies, including their associated benefits and limitations, is important for supporting the prolongation of survival in patients with advanced prostate cancer. Therefore, this section offers a valuable discussion on the treatment strategies for prostate cancer including CRPC.

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Conditional PTEN-deficient Mice as a Prostate Cancer Chemoprevention Model

Cited by 10 publications

References 25 publications

Generation of PTEN‑knockout (‑/‑) murine prostate cancer cells using the CRISPR/Cas9 system and comprehensive gene expression profiling

Generation of PTEN‑knockout (‑/‑) murine prostate cancer cells using the CRISPR/Cas9 system and comprehensive gene expression profiling

Withaferin A Inhibits Prostate Carcinogenesis in a PTEN-deficient Mouse Model of Prostate Cancer

Reconsideration of Hormonal Therapy in the Era of Next‐ Generation Hormonal Therapy

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