Deletion of<i>p21/Cdkn1a</i>confers protective effect against prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate model

Jain, Anil K.; Raina, Komal; Agarwal, Rajesh

doi:10.4161/cc.24741

Cited by 13 publications

(10 citation statements)

References 41 publications

(81 reference statements)

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“…In spite of their known function as CDK inhibitory proteins, P21Cip1 (Cdkn1a) and P16Ink4a (Cdkn2a) are shown to play crucial roles in accelerated cell proliferation in the TRAMP model [18]. In fact, Cdkn1a knockout completely blocks TRAMP carcinogenesis [19]. The much increased transcription of Cdkn2a was observed in DLP of TRAMP mice, consistent with the previous findings in TRAMP model [20].…”

Section: Resultssupporting

confidence: 81%

Gene expression signatures associated with suppression of TRAMP prostate carcinogenesis by a kavalactone‐rich Kava fraction

Tang

Zhang

Jiang

et al. 2016

Molecular Carcinogenesis

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Kava (Piper methysticum Forster) extract and its major kavalactones have been shown to block chemically induced lung tumor initiation in mouse models. Here we evaluated the chemopreventive effect of a kavalactone-rich Kava fraction B (KFB), free of flavokavains, on carcinogenesis in a transgenic adenocarcinoma of mouse prostate (TRAMP) model and characterized the prostate gene expression signatures. Male C57BL/6 TRAMP mice were fed AIN93M diet with or without 0.4% KFB from 8 wk of age. Mice were euthanized at 16 or 28 wk. The growth of the dorsolateral prostate (DLP) lobes in KFB-treated TRAMP mice was inhibited by 66% and 58% at the respective endpoint. Anterior and ventral prostate lobes in KFB-treated TRAMP mice were suppressed by 40% and 49% at 28 wk, respectively. KFB consumption decreased cell proliferation biomarker Ki-67 and epithelial lesion severity in TRAMP DLP, without detectable apoptosis enhancement. Real time qRT-PCR detection of mRNA from DLP at 28 wk showed decreased expression of cell cycle regulatory genes congruent with Ki-67 suppression. Microarray profiling of DLP mRNA indicated that "oncogene-like" genes related to angiogenesis and cell proliferation were suppressed by KFB but tumor suppressor, immunity, muscle/neuro, and metabolism-related genes were upregulated by KFB in both TRAMP and WT DLP. TRAMP mice fed KFB diet developed lower incidence of neuroendocrine carcinomas (NECa) (2 out of 14 mice) than those fed the basal diet (8 out of 14 mice, χ = 5.6, P < 0.025). KFB may, therefore, inhibit not only TRAMP DLP epithelial lesions involving multiple molecular pathways, but also NECa. © 2016 Wiley Periodicals, Inc.

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Section: Resultssupporting

confidence: 81%

Gene expression signatures associated with suppression of TRAMP prostate carcinogenesis by a kavalactone‐rich Kava fraction

Tang

Zhang

Jiang

et al. 2016

Molecular Carcinogenesis

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“…In the p21 −/− group, no incidence of moderately different (MD) tumors were seen, whereas 1/13 p21 +/− /TRAMP mice showed MD tumors. In comparison, 5/15, 6/15 and 3/15 TRAMP mice showed well differentiated, MD and poorly differentiated prostate adenocarcinoma lesions [126]. P21 is also associated with poor survival outcomes, higher recurrence and elevated Gleason scores [126].…”

Section: P21 Upregulationmentioning

confidence: 96%

“…In comparison, 5/15, 6/15 and 3/15 TRAMP mice showed well differentiated, MD and poorly differentiated prostate adenocarcinoma lesions [126]. P21 is also associated with poor survival outcomes, higher recurrence and elevated Gleason scores [126]. This contradictory outcome was attributed to the paracrine growth enhancing effect of p21 [126].…”

Section: P21 Upregulationmentioning

confidence: 99%

“…P21 is also associated with poor survival outcomes, higher recurrence and elevated Gleason scores [126]. This contradictory outcome was attributed to the paracrine growth enhancing effect of p21 [126]. A pro-mitogenic effect of p21 in conditioned media was seen in C8 cell line, a mouse embryo fibroblast cell line transformed by E1A and H-Ras [127].…”

Section: P21 Upregulationmentioning

confidence: 99%

“…Following HDAC inhibition, p21 levels have been upregulated in various cancers [126,128]. A plethora of studies highlight the role of p21 in cell cycle arrest in response to HDAC inhibition [102,103].…”

Section: P21 Upregulationmentioning

confidence: 99%

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Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

et al. 2020

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Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide. Histone deacetylase (HDAC) inhibitors showed promising results in hematological malignancies, but they failed in solid tumors such as prostate cancer, despite the overexpression of HDACs in CRPC. Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression. In this review, the pharmacodynamic reasons for the failure of HDAC inhibitors were assessed and placed in the context of the advancements in the understanding of CRPCs, HDACs and resistance mechanisms. The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.

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Essential role of SH3GL1 in interleukin-6(IL-6)- and vascular endothelial growth factor (VEGF)-triggered p130cas-mediated proliferation and migration of osteosarcoma cells

Zhang

2017

Human Cell

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We recently demonstrated that interleukin-6 (IL-6)- and vascular endothelial growth factor (VEGF)-induced osteosarcoma (OS) cell proliferation and migration are parallel to significant increased expression of SH3GL1 and the phosphorylation level of P130. The expression level of SH3GL1 was widely upregulated in human OS tissues, and their overexpression was significantly correlated with more aggressive clinicopathological features. Conversely, depletion of SH3GL1 by adenovirus shRNA abrogates P130 phosphorylation and IL-6- and VEGF-induced OS cell proliferation and migration. To further pinpoint the mechanism how SH3GL1 was responsible for cell proliferation and migration, we deleted SH3GL1 in vitro and in vivo. In vitro, depletion of SH3GL1 abrogates P130 phosphorylation and IL-6- and VEGF-induced OS cell proliferation and migration. SH3GL1 knockdown caused cell cycle arrest in G/G phase via downregulation of cyclin D1, caused activation of p27, and attenuated the activation of p-Rb. Interestingly, SH3GL1 knockdown also markedly attenuated the phosphorylation level of Akt/GSK-3β/FAK. In vivo, depletion of SH3GL1 by shRNA inhibited the tumor tissue growth and the expression of p-P130. Collectively, our results strongly suggest that SH3GL1 is a novel target for anti-osteosarcoma.

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Deletion ofp21/Cdkn1aconfers protective effect against prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate model

Cited by 13 publications

References 41 publications

Gene expression signatures associated with suppression of TRAMP prostate carcinogenesis by a kavalactone‐rich Kava fraction

Gene expression signatures associated with suppression of TRAMP prostate carcinogenesis by a kavalactone‐rich Kava fraction

Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

Essential role of SH3GL1 in interleukin-6(IL-6)- and vascular endothelial growth factor (VEGF)-triggered p130cas-mediated proliferation and migration of osteosarcoma cells

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