Function of PIN1 in Cancer Development and Its Inhibitors as Cancer Therapeutics

Abstract

Peptidyl-prolyl isomerase (PIN1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which results in the alteration of protein structure, function, and stability. The altered structure and function of these phosphorylated proteins regulated by PIN1 are closely related to cancer development. PIN1 is highly expressed in human cancers and promotes cancer as well as cancer stem cells by breaking the balance of oncogenes and tumor suppressors. In this review, we discuss the roles of PIN1 in cancer and PIN1-targeted small-molecule compounds.

Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy

“…An increasing body of evidence shows that β-catenin not only increases cell proliferation but also promotes migration and invasion in cancer cells [ 66 , 157 , 161 ]. Therefore, Pin1 promotes invasion, metastasis and even other malignant tumor processes partly through the upregulation of β-catenin-mediated signaling cascades [ 19 , 68 , 150 ]. Transforming growth factor (TGF)-β plays a critical role in tumor metastasis [ 162 , 163 , 164 , 165 ] and Pin1 has been found to upregulate TGF-β by stabilizing its mRNA [ 166 ].…”

“…The WW domain preferentially binds to pSer/Thr-Pro containing peptide sequences, while the catalytic domain isomerizes the prolyl bond in the pSer/Thr-Pro motif [ 14 , 16 ]. Pin1 was initially identified as being involved in cell cycle progression, but mounting evidence has shown that Pin1-mediated prolyl isomerization plays a crucial role in diverse biological processes, including cell cycle regulation, cell growth, differentiation, immune responses, stemness, and even tumorigenesis [ 8 , 17 , 18 , 19 ]. Moreover, Pin1 is commonly overexpressed in most cancers and high levels of Pin1 expression is correlated with poor prognosis in various cancers [ 10 , 11 , 20 , 21 , 22 , 23 , 24 ].…”

“…Moreover, Pin1 is commonly overexpressed in most cancers and high levels of Pin1 expression is correlated with poor prognosis in various cancers [ 10 , 11 , 20 , 21 , 22 , 23 , 24 ]. An increasing body of evidence has shown that Pin1 promotes tumor initiation, development, and resistance to cell death as well as enabling replicative immortality by upregulating oncogenes and proliferating-promoting factors or downregulating tumor suppressors and proliferation-suppressing factors [ 10 , 11 , 12 , 19 ]. Therefore, Pin1 is regarded as an intriguing target for cancer therapy.…”

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

“…Aberrant Pin1 elevation has been shown to be involved in many signaling events such as cell cycle coordination, chromosome instability, proliferation, migration, metastasis, and apoptosis in cancer (Zhou and Lu, 2016). Indeed, Pin1 is known to activate 56 oncogenes and inactivate 26 tumor suppressors by regulating their activity, protein interaction, stability, and cellular localization (Cheng and Tse, 2019;Yu et al, 2020). Pin1 overexpression in mammary gland induces chromosome instability and leads to breast cancer development and Pin1 ablation effectively prevents tumorigenesis by overexpressing Neu in animal models (Wulf et al, 2004;Suizu et al, 2006).…”

The Molecular ‘Myc-anisms’ behind Myc-Driven Tumorigenesis and the Relevant Myc-Directed Therapeutics

“…Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1), an isomerase that specifically recognizes the serine/threonine-proline motif, is overexpressed in several cancers including pancreatic, breast, and prostate and its expression correlates with poor clinical outcomes [ 129 , 130 , 131 ]. Furthermore, Pin1 promotes several hallmarks of cancer through inactivating 26 tumor suppressors and activating 56 oncogenes [ 132 , 133 ]. By catalyzing the cis/trans conformational change of the target protein, such as Myc, isomerases like Pin1 gain control of the target protein’s stability, activity, and localization [ 134 ].…”