Disorder, Promiscuous Interactions, and Stochasticity Regulate State Switching in the Unstable Prostate

Abstract

A causal link between benign prostatic hyperplasia (BPH) and prostate cancer has long been suspected but not widely accepted. A new model is proposed that supports such a connection. In contrast to the prevailing wisdom, our model, that draws on dynamical systems theory, suggests that in response to stress, epithelial cells in the unstable gland can give rise to both types of diseases via a phenotypic switching mechanism. The central idea is that phenotypic switching is a stochastic process which exploits the plasticity of the epithelial cell. It is driven by 'noise' contributed by the conformational dynamics of proteins that are intrinsically disordered. In a system that is noisy when stressed, disorder promotes promiscuity, unmasks latent information, and rewires the network to cause phenotypic switching. Cells with newly acquired phenotypes can transcend the traditional zonal boundaries to give rise to BPH or prostate cancer depending on the microenvironment. Establishing causality between the two diseases may provide us with an opportunity to better understand their etiology and guide prevention and treatment strategies. J. Cell. Biochem. 117: 2235-2240, 2016. © 2016 Wiley Periodicals, Inc.

Stromal‐epithelial interactions in prostate cancer: Overexpression of PAGE4 in stromal cells inhibits the invasive ability of epithelial cells

“…Interestingly, such a role for PAGE4 was postulated in attempting to establish a causal link between BPH and PCa. 3…”

“…1 More specifically, PAGE4 is a CT/X antigen (located on the X chromosome) and is one of the handful of CTAs that has been studied in considerable detail. 2,3 PAGE4 is remarkably prostate-specific and has the characteristics of proto-oncogene. Therefore, the PAGE4 protein is dramatically upregulated in the fetal prostate from gestational weeks ~8 to 27 both in the epithelial and stromal cells of the prostate buds but is undetectable in the fetal prostate at birth.…”

The Intrinsically Disordered N Terminus in Atg12 from Yeast Is Necessary for the Functional Structure of the Protein

“…Furthermore, numerous human diseases have an origin in dysfunctional IDPRs, making them an important therapeutic target [36][37][38][39][40][41]. The dynamic nature of IDPRs allows for a prompt protein conformational change that accommodates switching of binding partners [28,42]. IDPRs, lacking secondary and tertiary structure, are sensitive to proteolytic enzymes.…”

Prostate-Associated Gene 4 (PAGE4): Leveraging the Conformational Dynamics of a Dancing Protein Cloud as a Therapeutic Target

“…However, the authors cautioned that their data underscoring the coincidence of the two diseases should not be used to infer causality between the two. On the other hand, Kulkarni and Getzenberg [ 33 ] have argued that there could be a causal relationship between the two diseases.…”