Targeting prolyl isomerase Pin1 as a promising strategy to overcome resistance to cancer therapies.

The development of tumor therapeutic resistance is one of the important reasons for the failure of antitumor therapy. Starting with multiple targets and multiple signaling pathways is helpful in understanding the mechanism of tumor resistance. The overexpression of prolyl isomerase Pin1 is highly correlated with the malignancy of cancer, since Pin1 controls many oncogenes and tumor suppressors, as well as a variety of cancer-driving signaling pathways. Strikingly, numerous studies have shown that Pin1 is directly involved in therapeutic resistance. In this review, we mainly summarize the functions and mechanisms of Pin1 in therapeutic resistance of multifarious cancers, such as breast, liver, and pancreatic carcinomas. Furtherly, from the perspective of Pin1-driven cancer signaling pathways including Raf/MEK/ERK, PI3K/Akt, Wnt/ß-catenin, NF-κB, as well as Pin1 inhibitors containing juglone, epigallocatechin-3-gallate (EGCG), all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), it is better to demonstrate the important potential role and mechanism of Pin1 in resistance and sensitization to cancer therapies. It will provide new therapeutic approaches for clinical reversal and prevention of tumor resistance by employing synergistic administration of Pin1 inhibitors and chemotherapeutics, implementing combination therapy of Pin1-related cancer signaling pathway inhibitors and Pin1 inhibitors, and exploiting novel Pin1-specific inhibitors.

Genetic variants, neurocognitive outcomes, and functional neuroimaging in survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Genetic predispositions may modulate risk for developing neurocognitive late effects in childhood acute lymphoblastic leukemia (ALL) survivors. METHODS: Long-term ALL survivors (n = 212; mean = 14.3 [SD = 4.77] years; 49% female) treated with chemotherapy completed neurocognitive testing and task-based functional neuroimaging. Based on previous work from our team, genetic variants related to the folate pathway, glucocorticoid regulation, drug metabolism, oxidative stress, and attention were included as predictors of neurocognitive performance, using multivariable models adjusted for age, race, and sex. Subsequent analyses evaluated the impact of these variants on task-based functional neuroimaging. Statistical tests were 2-sided. RESULTS: Survivors exhibited higher rates of impaired attention (20.8%), motor skills (42.2%), visuo-spatial memory (49.3%-58.3%), processing speed (20.1%), and executive function (24.3%-26.1%) relative to population norms (10%; P < .001). Genetic variants implicated in attention deficit phenotypes predicted impaired attention span (synaptosome associated protein 25, F(2,172) = 4.07, P = .019) and motor skills (monoamine oxidase A, F(2,125) = 5.25, P = .007). Visuo-spatial memory and processing speed varied as a function of genetic variants in the folate pathway (methylenetetrahydrofolate reductase [MTHFRrs1801133], F(2,165) = 3.48, P = .033; methylenetetrahydrofolate dehydrogenase 1 [MTHFD1rs2236225], F(2,135) = 3.8, P = .025; respectively). Executive function performance was modulated by genetic variants in the folate pathway (MTHFD1rs2236225, F(2,158) = 3.95, P = .021; MTHFD1rs1950902, F(2,154) = 5.55, P = .005) and glucocorticoid regulation (vitamin D receptor, F(2,158) = 3.29, P = .039; FKBP prolyl isomerase 5, F(2,154) = 5.6, P = .005). Additionally, MTHFD1rs2236225 and FKBP prolyl isomerase 5 were associated with altered brain function during attention and working memory (P < .05; family wise error corrected). CONCLUSIONS: Results extend previous findings of genetic risk of neurocognitive impairment following ALL therapy and highlight the importance of examining genetic modulators in relation to neurocognitive deficits.

Peptidylprolyl Isomerases as In Vivo Carriers for Drugs That Target Various Intracellular Entities.

Analyses of sequences and structures of the cyclosporine A (CsA)-binding proteins (cyclophilins) and the immunosuppressive macrolide FK506-binding proteins (FKBPs) have revealed that they exhibit peculiar spatial distributions of charges, their overall hydrophobicity indexes vary within a considerable level whereas their points isoelectric (pIs) are contained from 4 to 11. These two families of peptidylprolyl cis/trans isomerases (PPIases) have several distinct functional attributes such as: (1) high affinity binding to some pharmacologically-useful hydrophobic macrocyclic drugs; (2) diversified binding epitopes to proteins that may induce transient manifolds with altered flexibility and functional fitness; and (3) electrostatic interactions between positively charged segments of PPIases and negatively charged intracellular entities that support their spatial integration. These three attributes enhance binding of PPIase/pharmacophore complexes to diverse intracellular entities, some of which perturb signalization pathways causing immunosuppression and other system-altering phenomena in humans.

Could Pin1 help us conquer essential hypertension at an earlier stage? A promising early-diagnostic biomarker and its therapeutic implications for the disease.

Essential hypertension is a major risk factor for cardiovascular morbidity and mortality, and the early-diagnosis is very important for the prevention of essential hypertension. Previously, we found that Pin1, the only known enzyme isomerizing pSer/pThr-Pro motifs in proteins, may gradually become inactive under conditions of stress such as intracellular acidification and fever. Interestingly, essential hypertension and the dysfunction of Pin1 often synchronously occur with the increasing age. Recent evidence indicates that Pin1 primarily increases the activity of endothelial nitric oxide synthase (eNOS) and the production of nitric oxide (NO) in multiple ways, significantly promoting the relaxation response of blood vessels and preventing the elevation of blood pressure. Further, the inhibition of Pin1 results in significantly increased blood pressure in rats. So, we hypothesized and evaluated the potential of Pin1 to be a new early-diagnostic biomarker as well as a therapeutic drug for essential hypertension. The unique activity of Pin1 and some epidemiological and experimental data evidence that the decreased activity of Pin1 may be closely associated with the development of essential hypertension. The factors that may impact the activity of Pin1 and correlate with the risk of essential hypertension were also discussed. These findings indicate that Pin1 plays a key and permanent role in efficiently preventing the development of essential hypertension, and that Pin1 may be a promising early-diagnostic biomarker as well as an effective therapeutic drug for the early-diagnosis, prevention, and treatment of essential hypertension, potentially decreasing the risk of cardiovascular morbidity and mortality.

Co-expression and immunity of Legionella pneumophila mip gene and immunoadjuvant ctxB gene.

The mip gene of Legionella pneumophila and the ctxB gene of Vibrio cholerae were amplified by PCR respectively. The amplified cDNA was ligated to the pcDNA3.1(+) vector. The recombinant plasmids pcDNA3.1-mip and pcDNA3.1-ctxB were identified by restriction analysis and PCR, and further confirmed by sequencing analysis. NIH3T3 cells were transfected with pcDNA3.1-mip and pcDNA3.1-ctxB according to the Lipofection method. Transient and stable products of the co-expression of the mip gene and ctxB gene were detected by immunofluorescence and Western blotting. The results showed that NIH3T3 cells were successfully transfected, and that the transiently and stably co-expressed products can be detected in the transfected cells. To detect the humoral and cellular immune response in immunized mice induced by the co-mmunization of the mip and ctxB genes, female BALB/c mice were immunized intramuscularly with pcDNA3.1-mip and pcDNA3.1-ctxB. The results showed that the specific antibody titer and the cytotoxic T-lymphocyte response for pcDNA3.1-mip immunization and co-immunization were increased compared with that of pcDNA3.1(+) immunization. Furthermore, the specific antibody titer and cytotoxic T-lymphocyte response for co-immunization were increased compared with that of pcDNA3.1-mip immunization. Statistical analysis using one-way analysis of variance (ANOVA) showed that there was a significant difference between the groups (P<0.01). The results indicated that the ctxB gene enhanced the humoral and cellular immune response to the mip gene immunization. These findings provide experimental evidence to support the development of the L. pneumophila DNA vaccine.

[Understanding of molecular pathogenesis of Alzheimer's disease: implications for drug development].

Recent advances in the knowledge about Alzheimer pathogenesis indicate several tactics for the development of drugs to treat Alzheimer's disease. Firstly, the function of presenilin, the causative gene for most familial Alzheimer's disease, has been demonstrated to be the protease in the Notch signaling system. Presenilin cleaves the transmembrane domain of the C-terminal fragment of the Notch-1 molecule, which is generated by proteolysis by furin-like proteases. APP is also cleaved by presenilin at the gamma cut site, implying that presenilin is gamma-secretase itself or at least closely functioning with gamma-secretase. A recent paper has demonstrated that immunization of APP transgenic mouse with amyloid beta 42 may decrease and prevent amyloid deposition in brain tissue. This unique and novel approach may open the new tactics for developing anti-dementia drugs. Another important finding comes from the identification of the function of prolyl isomerase. It is demonstrated that pin 1, intra-nuclear prolyl isomerase, can restore the microtubule binding capacity of phosphorylated tau, which clearly shows a solid strategy for developing drugs for preventing neuronal degeneration.