Pin1 Inhibitor Juglone Exerts Anti-Oncogenic Effects on LNCaP and DU145 Cells despite the Patterns of Gene Regulation by Pin1 Differing between These Cell Lines

Kanaoka, Ryuhei; Kushiyama, Akifumi; Seno, Yasuyuki; Nakatsu, Yusuke; Matsunaga, Yasuka; Fukushima, Toshiaki; Tsuchiya, Y.; Sakoda, Hideyuki; Fujishiro, Midori; Yamamotoya, Takeshi; Kamata, Hideaki; Matsubara, Akio; Asano, Tomohiko

doi:10.1371/journal.pone.0127467

Cited by 22 publications

(18 citation statements)

References 58 publications

(47 reference statements)

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“…Inhibition of PIN1 prolyl isomerase activity with therapeutic compounds, such as juglone or PiB (diethyl-1,3,6,8tetrahydro-1,3,6,8-tetraoxobenzo[lmn]3, 8 phenanthroline-2,7-diacetate), have shown efficacy in a variety of tumors [153][154][155][156][157][158][159][160]. However, both of these compounds are able to reduce proliferation in a Pin1 null mouse, indicating that PIN1 is not their only target [158,161].…”

Section: Pin1 Inhibitionmentioning

confidence: 99%

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Allen-Petersen¹,

Sears²

2019

BioDrugs

125

103

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MYC is a master transcriptional regulator that controls almost all cellular processes. Over the last several decades, researchers have strived to define the context-dependent transcriptional gene programs that are controlled by MYC, as well as the mechanisms that regulate MYC function, in an effort to better understand the contribution of this oncoprotein to cancer progression. There are a wealth of data indicating that deregulation of MYC activity occurs in a large number of cancers and significantly contributes to disease progression, metastatic potential, and therapeutic resistance. Although the therapeutic targeting of MYC in cancer is highly desirable, there remain substantial structural and functional challenges that have impeded direct MYC-targeted drug development and efficacy. While efforts to drug the 'undruggable' may seem futile given these challenges and considering the broad reach of MYC, significant strides have been made to identify points of regulation that can be exploited for therapeutic purposes. These include targeting the deregulation of MYC transcription in cancer through small-molecule inhibitors that induce epigenetic silencing or that regulate the G-quadruplex structures within the MYC promoter. Alternatively, compounds that disrupt the DNA-binding activities of MYC have been the long-standing focus of many research groups, since this method would prevent downstream MYC oncogenic activities regardless of upstream alterations. Finally, proteins involved in the post-translational regulation of MYC have been identified as important surrogate targets to reduce MYC activity downstream of aberrant cell stimulatory signals. Given the complex regulation of the MYC signaling pathway, a combination of these approaches may provide the most durable response, but this has yet to be shown. Here, we provide a comprehensive overview of the different therapeutic strategies being employed to target oncogenic MYC function, with a focus on post-translational mechanisms.

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Section: Pin1 Inhibitionmentioning

confidence: 99%

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Allen-Petersen¹,

Sears²

2019

BioDrugs

125

103

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“…4). Many therapeutic studies for treating cancers have developed Pin1 inhibitors based on the fact that Pin1 is a generally recognized tumor-promoting factor [213][214][215][216][217][218][219][220][221][222][223][224][225][226]. Considering that Pin1 has also been reported to have a tumor suppressing function, Pin1-directed inhibitors must be carefully implicated in cancers.…”

Section: Pin1mentioning

confidence: 99%

Molecular crosstalk between cancer and neurodegenerative diseases

Seo

Park

2019

Cell. Mol. Life Sci.

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The progression of cancers and neurodegenerative disorders is largely defined by a set of molecular determinants that are either complementarily deregulated, or share remarkably overlapping functional pathways. A large number of such molecules have been demonstrated to be involved in the progression of both diseases. In this review, we particularly discuss our current knowledge on p53, cyclin D, cyclin E, cyclin F, Pin1 and protein phosphatase 2A, and their implications in the shared or distinct pathways that lead to cancers or neurodegenerative diseases. In addition, we focus on the interdependent regulation of brain cancers and neurodegeneration, mediated by intercellular communication between tumor and neuronal cells in the brain through the extracellular microenvironment. Finally, we shed light on the therapeutic perspectives for the treatment of both cancer and neurodegenerative disorders. Keywords Age-related diseases • Cell death • Cell survival • Redox system • Glioma • Neurotoxicity Abbreviations Aβ Amyloid-β AD Alzheimer's disease ALS Amyotrophic lateral sclerosis AMPA α-Amino-3-hydroxy-5-methyl-4isoxazolepropionate APC/C Anaphase promoting complex/ cyclosome APP Amyloid precursor protein ATRA All-trans retinoic acid APL Acute promyelocytic leukemia Bax Bcl-2 associated X BH3 Bcl-2 homology 3 Bim Bcl-2-interacting mediator of cell death BimEL Bim-extra long CDK Cyclin-dependent kinase Cellular and Molecular Life Sciences

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“…This proteomic selectivity for Pin1 allowed us to show that short-term Pin1 inhibition does not induce cytotoxicity, despite previous results reported with less selective inhibitors 39,[97][98][99][100][101][102] .…”

Section: Discussionmentioning

confidence: 64%

Sulfopin, a selective covalent inhibitor of Pin1, blocks Myc-driven tumor initiation and growthin vivo

Dubiella

Zaidman

et al. 2020

Preprint

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The peptidyl-prolyl cis-trans isomerase, Pin1, acts as a unified signaling hub that is exploited in cancer to activate oncogenes and inactivate tumor suppressors, in particular through up-regulation of c-Myc target genes. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to discover covalent inhibitors targeting Pin1's active site nucleophile -Cys113, leading to the development of Sulfopin, a double-digit nanomolar Pin1 inhibitor. Sulfopin is highly selective for Pin1, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement, and phenocopies genetic knockout of Pin1. Although Pin1 inhibition had a modest effect on viability in cancer cell cultures, Sulfopin induced downregulation of c-Myc target genes and reduced tumor initiation and tumor progression in murine and zebrafish models of MYCN-driven neuroblastoma. Our results suggest that Sulfopin is a suitable chemical probe for assessing Pin1dependent pharmacology in cells and in vivo. Moreover, these studies indicate that Pin1 should be further investigated as a potential cancer target.

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Pin1 Inhibitor Juglone Exerts Anti-Oncogenic Effects on LNCaP and DU145 Cells despite the Patterns of Gene Regulation by Pin1 Differing between These Cell Lines

Cited by 22 publications

References 58 publications

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Molecular crosstalk between cancer and neurodegenerative diseases

Sulfopin, a selective covalent inhibitor of Pin1, blocks Myc-driven tumor initiation and growthin vivo

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