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Inhibition of peptidyl-prolyl isomerase (PIN1) and BRAF signaling to target melanoma.

ABSTRACT: PIN1 is a phosphorylation-dependent peptidyl-prolyl cis/trans isomerase, overexpressed in many cancers, including melanoma. Our immunohistochemistry data of melanoma patient tissue underline the up-regulation of PIN1 in metastases. Here, we demonstrate important functions of PIN1 and its selective and cell permeable inhibitor 37 for the treatment of melanoma. To analyze its possible role in oncogenesis and as a therapeutic target, we first suppressed PIN1 expression by a siRNA pool. PIN1 knockdown potently inhibited melanoma cell proliferation and vascular mimicry by influencing several cancer-relevant pathways. Furthermore, inhibitor 37 inhibited cell growth in melanoma and induced apoptosis. Normal healthy melanocytes, keratinocytes and fibroblasts are not affected by the PIN1 inhibitor 37. Combinatorial treatment of melanoma cells is with Vemurafenib as a common therapeutic option for BRAF-mutated melanoma and inhibitor 37 resulted in a strong, synergistic effect on apoptosis of melanoma cell lines. In summary, targeting PIN1 offers a promising therapeutic approach to simultaneously downregulate multiple cancer-driving pathways in cancer.

SUBMITTER: Braun C

PROVIDER: S-EPMC6684922 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The Peptidyl-prolyl Isomerase Pin1 in Neuronal Signaling: from Neurodevelopment to Neurodegeneration.

Project description:The peptidyl-prolyl isomerase Pin1 is a unique enzyme catalyzing the isomerization of the peptide bond between phosphorylated serine-proline or threonine-proline motifs in proteins, thereby regulating a wide spectrum of protein functions, including folding, intracellular signaling, transcription, cell cycle progression, and apoptosis. Pin1 has been reported to act as a key molecular switch inducing cell-type-specific effects, critically depending on the different phosphorylation patterns of its targets within different biological contexts. While its implication in proliferating cells, and, in particular, in the field of cancer, has been widely characterized, less is known about Pin1 biological functions in terminally differentiated and post-mitotic neurons. Notably, Pin1 is widely expressed in the central and peripheral nervous system, where it regulates a variety of neuronal processes, including neuronal development, apoptosis, and synaptic activity. However, despite studies reporting the interaction of Pin1 with neuronal substrates or its involvement in specific signaling pathways, a more comprehensive understanding of its biological functions at neuronal level is still lacking. Besides its implication in physiological processes, a growing body of evidence suggests the crucial involvement of Pin1 in aging and age-related and neurodegenerative diseases, including Alzheimer's disease, Parkinson disease, frontotemporal dementias, Huntington disease, and amyotrophic lateral sclerosis, where it mediates profoundly different effects, ranging from neuroprotective to neurotoxic. Therefore, a more detailed understanding of Pin1 neuronal functions may provide relevant information on the consequences of Pin1 deregulation in age-related and neurodegenerative disorders.

| S-EPMC7878263 | biostudies-literature

Non-catalytic participation of the Pin1 peptidyl-prolyl isomerase domain in target binding.

Project description:Pin1 is a phosphorylation-dependent peptidyl-prolyl isomerase (PPIase) that has the potential to add an additional level of regulation within protein kinase mediated signaling pathways. Furthermore, there is a mounting body of evidence implicating Pin1 in the emergence of pathological phenotypes in neurodegeneration and cancer through the isomerization of a wide variety of substrates at peptidyl-prolyl bonds where the residue preceding proline is a phosphorylated serine or threonine residue (i.e., pS/T-P motifs). A key step in this regulatory process is the interaction of Pin-1 with its substrates. This is a complex process since Pin1 is composed of two domains, the catalytic PPIase domain, and a type IV WW domain, both of which recognize pS/T-P motifs. The observation that the WW domain exhibits considerably higher binding affinity for pS/T-P motifs has led to predictions that the two domains may have distinct roles in mediating the actions of Pin1 on its substrates. To evaluate the participation of its individual domains in target binding, we performed GST pulldowns to monitor interactions between various forms of Pin1 and mitotic phospho-proteins that revealed two classes of Pin-1 interacting proteins, differing in their requirement for residues within the PPIase domain. From these observations, we consider models for Pin1-substrate interactions and the potential functions of the different classes of Pin1 interacting proteins. We also compare sequences that are recognized by Pin1 within its individual interaction partners to investigate the underlying basis for its different types of interactions.

| S-EPMC3571201 | biostudies-literature

Post-translational Modifications of the Peptidyl-Prolyl Isomerase Pin1.

Project description:The peptidyl-prolyl cis/trans isomerase (PPIase) Pin1 is a unique enzyme that only binds to Ser/Thr-Pro peptide motifs after phosphorylation and regulates the conformational changes of the bond. The Pin1-catalyzed isomerization upon phosphorylation can have profound effects on substrate biological functions, including their activity, stability, assembly, and subcellular localization, affecting its role in intracellular signaling, transcription, and cell cycle progression. The functions of Pin1 are regulated by post-translational modifications (PTMs) in many biological processes, which include phosphorylation, ubiquitination, SUMOylation and oxidation. Phosphorylation of different Pin1 sites regulates Pin1 enzymatic activity, binding ability, localization, and ubiquitination by different kinases under various cellular contexts. Moreover, SUMOylation and oxidation have been shown to downregulate Pin1 activity. Although Pin1 is tightly regulated under physiological conditions, deregulation of Pin1 PTMs contributes to the development of human diseases including cancer and Alzheimer's disease (AD). Therefore, manipulating the PTMs of Pin1 may be a promising therapeutic option for treating various human diseases. In this review, we focus on the molecular mechanisms of Pin1 regulation by PTMs and the major impact of Pin1 PTMs on the progression of cancer and AD.

| S-EPMC7064559 | biostudies-literature

Peptidyl-Prolyl Cis/Trans Isomerase Pin1 and Alzheimer's Disease.

Project description:Alzheimer's disease (AD) is the most common cause of dementia with cognitive decline. The neuropathology of AD is characterized by intracellular aggregation of neurofibrillary tangles consisting of hyperphosphorylated tau and extracellular deposition of senile plaques composed of beta-amyloid peptides derived from amyloid precursor protein (APP). The peptidyl-prolyl cis/trans isomerase Pin1 binds to phosphorylated serine or threonine residues preceding proline and regulates the biological functions of its substrates. Although Pin1 is tightly regulated under physiological conditions, Pin1 deregulation in the brain contributes to the development of neurodegenerative diseases, including AD. In this review, we discuss the expression and regulatory mechanisms of Pin1 in AD. We also focus on the molecular mechanisms by which Pin1 controls two major proteins, tau and APP, after phosphorylation and their signaling cascades. Moreover, the major impact of Pin1 deregulation on the progression of AD in animal models is discussed. This information will lead to a better understanding of Pin1 signaling pathways in the brain and may provide therapeutic options for the treatment of AD.

| S-EPMC7243138 | biostudies-literature

A Selective, Cell-Permeable Nonphosphorylated Bicyclic Peptidyl Inhibitor against Peptidyl-Prolyl Isomerase Pin1.

Project description:Pin1 regulates the levels and functions of phosphoproteins by catalyzing phosphorylation-dependent cis/trans isomerization of peptidyl-prolyl bonds. Previous Pin1 inhibitors contained phosphoamino acids, which are metabolically unstable and have poor membrane permeability. In this work, we report a cell-permeable and metabolically stable nonphosphorylated bicyclic peptide as a potent and selective Pin1 inhibitor, which inhibited the intracellular Pin1 activity in cultured mammalian cells but had little effect on other isomerases such as Pin4, FKBP12, or cyclophilin A.

| S-EPMC4594195 | biostudies-literature

Peptidyl-prolyl cis/trans-isomerase A1 (Pin1) is a target for modification by lipid electrophiles.

Project description:Oxidation of membrane phospholipids is associated with inflammation, neurodegenerative disease, and cancer. Oxyradical damage to phospholipids results in the production of reactive aldehydes that adduct proteins and modulate their function. 4-Hydroxynonenal (HNE), a common product of oxidative damage to lipids, adducts proteins at exposed Cys, His, or Lys residues. Here, we demonstrate that peptidyl-prolyl cis/trans-isomerase A1 (Pin1), an enzyme that catalyzes the conversion of the peptide bond of pSer/pThr-Pro moieties in signaling proteins from cis to trans, is highly susceptible to HNE modification. Incubation of purified Pin1 with HNE followed by MALDI-TOF/TOF mass spectrometry resulted in detection of Michael adducts at the active site residues His-157 and Cys-113. Time and concentration dependencies indicate that Cys-113 is the primary site of HNE modification. Pin1 was adducted in MDA-MB-231 breast cancer cells treated with 8-alkynyl-HNE as judged by click chemistry conjugation with biotin followed by streptavidin-based pulldown and Western blotting with anti-Pin1 antibody. Furthermore, orbitrap MS data support the adduction of Cys-113 in the Pin1 active site upon HNE treatment of MDA-MB-231 cells. siRNA knockdown of Pin1 in MDA-MB-231 cells partially protected the cells from HNE-induced toxicity. Recent studies indicate that Pin1 is an important molecular target for the chemopreventive effects of green tea polyphenols. The present study establishes that it is also a target for electrophilic modification by products of lipid peroxidation.

| S-EPMC3579456 | biostudies-literature

Pathologic role of peptidyl-prolyl isomerase Pin1 in pulmonary artery remodeling.

Project description:Peptidyl-prolyl isomerase Pin1 is crucial for cell proliferation, but its role in pulmonary artery remodeling (PAR) is unclear. In the present study, we aimed to evaluate the expression and contribution of Pin1 in PAR. Treatment with Pin1 inhibitor Juglone or Pin1-specific siRNAs ameliorated the expression of Pin1 and proliferating cell nuclear antigen (PCNA) in human pulmonary artery smooth muscle cells (PASMCs) in vitro, and Juglone treatment arrested the cell cycle at the G1 phase. Treatment with transforming growth factor β1 (TGF-β1) also enhanced Pin1 expression and PASMC proliferation. Immunohistochemical staining revealed that Pin1 and PCNA expression levels were increased and positively correlated with each other in PAR samples from humans and monocrotaline-treated Sprague-Dawley rats; these proteins were mainly localized in arteries undergoing remodeling, as well as inflammatory cells, and hyperplastic bronchial epithelial cells. Intraperitoneal injection of Juglone also led to morphologic and hemodynamic changes in PAR rats. Additionally, PAR rats displayed higher serum and lung TGF-β1 levels compared with controls, while administration of Juglone to PAR rats suppressed serum and lung TGF-β1 levels. The findings in this study suggest that TGF-β1 and Pin1 constitute a positive feedback loop, which plays an important role in the pathophysiology of PAR.

| S-EPMC8581927 | biostudies-literature

Regulation of eukaryotic protein kinases by Pin1, a peptidyl-prolyl isomerase.

Project description:The peptidyl-prolyl isomerase Pin1 cooperates with proline-directed kinases and phosphatases to regulate multiple oncogenic pathways. Pin1 specifically recognizes phosphorylated Ser/Thr-Pro motifs in proteins and catalyzes their cis-trans isomerization. The Pin1-catalyzed conformational changes determine the stability, activity, and subcellular localization of numerous protein substrates. We conducted a survey of eukaryotic protein kinases that are regulated by Pin1 and whose Pin1 binding sites have been identified. Our analyses reveal that Pin1 target sites in kinases do not fall exclusively within the intrinsically disordered regions of these enzymes. Rather, they fall into three groups based on their location: (i) within the catalytic kinase domain, (ii) in the C-terminal kinase region, and (iii) in regulatory domains. Some of the kinases downregulated by Pin1 activity are tumor-suppressing, and all kinases upregulated by Pin1 activity are functionally pro-oncogenic. These findings further reinforce the rationale for developing Pin1-specific inhibitors as attractive pharmaceuticals for cancer therapy.

| S-EPMC9992314 | biostudies-literature

Cellular peptidyl-prolyl cis/trans isomerase Pin1 facilitates replication of feline coronavirus.

Project description:Although feline coronavirus (FCoV) causes feline infectious peritonitis (FIP), which is a fatal infectious disease, there are no effective therapeutic medicines or vaccines. Previously, in vitro studies have shown that cyclosporin (CsA) and FK506 inhibit virus replication in diverse coronaviruses. CsA and FK506 are targets of clinically relevant immunosuppressive drugs and bind to cellular cyclophilins (Cyps) or FK506 binding proteins (FKBPs), respectively. Both Cyp and FKBP have peptidyl-prolyl cis-trans isomerase (PPIase) activity. However, protein interacting with NIMA (Pin1), a member of the parvulin subfamily of PPIases that differs from Cyps and FKBPs, is essential for various signaling pathways. Here we demonstrated that genetic silencing or knockout of Pin1 resulted in decreased FCoV replication in vitro. Dipentamethylene thiuram monosulfide, a specific inhibitor of Pin1, inhibited FCoV replication. These data indicate that Pin1 modulates FCoV propagation.

| S-EPMC7113879 | biostudies-literature

The peptidyl-prolyl isomerase PIN1 relieves cyclin-dependent kinase 2 (CDK2) inhibition by the CDK inhibitor p27.

Project description:PIN1 is a peptidyl-prolyl isomerase that catalyzes the cis/trans isomerization of peptide bonds between proline and phosphorylated serine/threonine residues. By changing the conformation of its protein substrates, PIN1 increases the activities of key proteins that promote cell cycle progression and oncogenesis. Moreover, it has been shown that PIN1 stabilizes and increases the level of the cyclin-dependent kinase (CDK) inhibitor p27, which inhibits cell cycle progression by binding cyclin A- and cyclin E-CDK2. Notwithstanding the associated increase in the p27 level, PIN1 expression promotes rather than retards cell proliferation. To explain the paradoxical effects of PIN1 on p27 levels and cell cycle progression, we hypothesized that PIN1 relieves CDK2 inhibition by suppressing the CDK inhibitory activity of p27. Here, we confirmed that PIN1-expressing cells exhibit higher p27 levels but have increased CDK2 activities and higher proliferation rates in the S-phase compared with Pin1-null fibroblasts or PIN1-depleted hepatoma cells. Using co-immunoprecipitation and CDK kinase activity assays, we found that PIN1 binds the phosphorylated Thr187-Pro motif in p27 and reduces p27's interaction with cyclin A- or cyclin E-CDK2, leading to increased CDK2 kinase activity. In conclusion, our results indicate that although PIN1 increases p27 levels, it also attenuates p27's inhibitory activity on CDK2 and thereby contributes to increased G1-S phase transitions and cell proliferation.

| S-EPMC5766953 | biostudies-literature

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