Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease

Abstract

BACKGROUND Pin1 is an intracellular signaling molecule which plays a critical but opposite role in the pathogenesis of Alzheimer’s disease (AD) and many human cancers. SCOPE OF REVIEW We review the structure and function of the Pin1 enzyme, the diverse roles it plays in cycling cells and neurons, the epidemiologic evidence for the inverse association between cancer and AD, and the potential therapeutic implications of Pin1-based therapies. MAJOR CONCLUSIONS Pin1 is a unique enzyme that has effects the function of target proteins by “twisting” them into different shapes. Cycling cells use Pin1 to help coordinate cell division. It is over-expressed and/or activated by multiple mechanisms in many common human cancers, and acts on multiple signal pathways to promote tumorigenesis. Inhibition of Pin1 in animal models has profound anti-tumor effects. In contrast, Pin1 is down-regulated or inactivated by multiple mechanisms in AD brains. The absence of Pin1 impairs tau function and amyloid precursor protein processing, leading to tangle- and amyloid-related pathologies and neurodegeneration in an age-dependent manner, resembling human AD. We have developed cis and trans conformation-specific antibodies to provide the first direct evidence that tau exists in distinct cis and trans conformations and that Pin1 accelerates its cis to trans conversion, thereby protecting against tangle formation in AD. GENERAL SIGNIFICANCE Available studies on Pin1 suggest that cancer and AD may share biological pathways that are deregulated in different directions. Pin1 biology opens exciting preventive and therapeutic horizons for both cancer and neurodegeneration.

Neuroanatomical Distribution of DEK Protein in Corticolimbic Circuits Associated with Learning and Memory in Adult Male and Female Mice

“…Although this is the first study to suggest an association between the DEK oncogene and cognitive dysfunction, the link between cancer and Alzheimer’s disease has been proposed. In short, epidemiological data suggests an inverse transcriptional profile between cancer and neurodegenerative diseases, like Alzheimer’s (Driver et al 2015, Lanni et al 2012, McShea et al 2007, Pavlides et al 2010, Raina et al 2000, Zhu et al 2000). For example, cancer is associated with increased cellular proliferation (Stopper et al 2003), decreased apoptosis (Gerl & Vaux 2005), up-regulation of the canonical Wnt-pathway (Segditsas & Tomlinson 2006, Zhan et al 2017), while Alzheimer’s disease is associated with DNA damage (Coppede & Migliore 2009, Lovell & Markesbery 2007), decreased neurogenesis (Demars et al 2010), apoptosis (Smale et al 1995), and down-regulation of the canonical Wnt-pathway (Riise et al 2015).…”

Interaction of p53 with prolyl isomerases: Healthy and unhealthy relationships

“…In other neurodegenerative disorders the activity of Pin1 clearly gives rise to opposite outcomes [67,69]. In particular, in neurons of Alzheimer's Disease (AD) patients, Pin1 has been reported to be delocalized, inactivated or down-regulated [43,146,147], and its reduced activity has been associated with the emergence of age-related neurodegeneration in mice [139].…”

“…However, perturbation in signaling pathways and/or deregulated Pin1 expression or activity may amplify pathologic conditions such as cancer and neurodegenerative diseases that depend on these cues [42,68,69].…”

Prolyl isomerase Pin1 and neurotrophins: a loop that may determine the fate of cells in cancer and neurodegeneration

“…Accordingly, tentative explanations for ADcancer 'inverse comorbidity' have been proposed with both Pin1 [Driver et al 2015] and neurotrophin dysregulation [Krüttgen et al 2006]. The possible relationship between neurotrophins and Pin1 can be depicted further by analyzing the signal transduction pathways activated by these proteins.…”