Abstract
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity.
Highlights
Cells respond to extracellular and intracellular stimuli and elicit various regulatory mechanisms such as epigenetic regulations, allosteric regulations and post-translational modifications (PTMs) to control signal transduction [1,2,3]
Phosphorylation of serine or threonine residues preceding a proline is one of the most frequent PTMs and it occurs in a wide range of proteins which are usually involved in cell cycle progression in eukaryotic cells [5,6]
This modification is catalyzed by proline-directed kinases, which include cyclin-dependent protein kinases (CDKs), mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases (ERKs)/c-Jun N-terminal kinases (JNKs)/p38 mitogen-activated protein kinases (p38 MAPKs), glycogen synthase kinase-3 (GSK3) and polo-like kinases (PLKs) [7,8]
Summary
Cells respond to extracellular and intracellular stimuli and elicit various regulatory mechanisms such as epigenetic regulations, allosteric regulations and post-translational modifications (PTMs) to control signal transduction [1,2,3]. Phosphorylation of serine or threonine residues preceding a proline (pSer/Thr-Pro) is one of the most frequent PTMs and it occurs in a wide range of proteins which are usually involved in cell cycle progression in eukaryotic cells [5,6] This modification is catalyzed by proline-directed kinases, which include cyclin-dependent protein kinases (CDKs), mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases (ERKs)/c-Jun N-terminal kinases (JNKs)/p38 mitogen-activated protein kinases (p38 MAPKs), glycogen synthase kinase-3. Biomedicines 2021, 9, 359 configuration; the configuration switch of its peptide bonds is tightly controlled by prolyl cis-trans isomerization and plays a critical role in multiple cellular processes [8]. Peptidyl-prolyl cistrans isomerase NIMA-interacting 1 (Pin1), a member of the parvulin subfamily, is a unique enzyme that binds and isomerizes phosphorylated serine-proline or phosphorylated threonine-proline (pSer/Thr-Pro) motifs, thereby controlling diverse biological processes [8,10,11,12]. Pin is a desirable pharmaceutical target for cancer therapy, and the present study summarizes the recent progress of Pin1-targeted small-molecule compounds for cancer therapy
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