cyclin-d1 and juglone

Nasopharyngeal carcinoma (NPC) is a peculiar Epstein Barr virus (EBV)-associated malignancy that is prevalent in South-East Asia. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) isomerizes specific phosphorylated amino acid residues, which makes it an important regulator in cell survival and apoptosis. In this study, we investigated the contribution made by PIN1 in NPC tumorigenesis and PIN1's potential role as a therapeutic target.. The expression of PIN1 was examined in a panel of NPC cell lines, xenografts and primary tumors. The functional roles of PIN1 in NPC cells were elucidated by the knockdown and overexpression of PIN1 in in vitro and in vivo nude mice models by siRNA and lenti-viral transfection, respectively. The antitumor effects of the PIN1 inhibitor Juglone in NPC cells were also evaluated.. We revealed the consistent overexpression of PIN1 in almost all EBV-associated NPC cell lines, xenografts and primary tumors. PIN1 suppression was capable of inhibiting cyclin D1 expression and activating caspase-3 in NPC cells. It positively regulated NPC cell proliferation, colony formation and anchorage-independent growth. The inhibition of PIN1 suppressed tumor growth in vitro and in vivo.. This study demonstrates the oncogenic role of PIN1 in NPC tumorigenesis, and shows that its overexpression can enhance tumor cell growth via the upregulation of cyclinD1. Our findings inform the development of novel treatments targeting PIN1 for NPC patients.

Topics: Animals; Carcinoma; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Female; HeLa Cells; Herpesvirus 4, Human; Humans; Immunohistochemistry; In Vitro Techniques; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Naphthoquinones; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; NIMA-Interacting Peptidylprolyl Isomerase; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

In Alzheimer's disease, the peptidyl prolyl cis/trans isomerase Pin1 binds to phospho-Thr231 on Tau proteins and, hence, is found within degenerating neurons, where it is associated to the large amounts of abnormally phosphorylated Tau proteins. Conversely, Pin1 may restore the tubulin polymerization function of these hyperphosphorylated Tau. In the present work, we investigated, both at the cellular and molecular levels, the role of Pin1 in Alzheimer's disease through the study of its interactions with phosphorylated Tau proteins. We also showed that in neuronal cells, Pin1 upregulates the expression of cyclin D1. This, in turn, could facilitate the transition from quiescence to the G1 phase (re-entry in cell cycle) in a neuron and, subsequently, neuronal dedifferentiation and apoptosis. The involvement of Pin1 in the G0/G1 transition in neurons points to its function as a good target for the development of new therapeutic strategies in neurodegenerative disorders.

Topics: Alzheimer Disease; Cell Line; Cyclin D1; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Naphthoquinones; Neuroblastoma; Neurons; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Phosphopyruvate Hydratase; Phosphorylation; Protein Binding; Protein Structure, Tertiary; Spectrometry, Fluorescence; tau Proteins