Does TGF-b induced formation of actin stress fibres reinforce Smad dependent TGF-b signalling in the prostate? Stephen Assinder a,⇑ , Nicholas Cole b a Physiology, Bosch Institute, School of Medical Sciences, University of Sydney, NSW 2006, Australia b Anatomy, Bosch Institute, School of Medical Sciences, University of Sydney, NSW 2006, Australia article info Article history: Received 25 August 2010 Accepted 14 February 2011 abstract In the normal prostate, and during early stages of prostate cancer (PCa) development, the cytokine trans- forming growth factor beta (TGF-b) acts as a tumour suppressor by inducing cytostasis and apoptosis. However, during tumour development these Smad signalling-dependent endpoints are lost in favour of Smad-independent tumourigenic actions of TGF-b. In this working hypothesis we present an argument for an intimate association between the TGF-b signalling pathway and the actin cytoskeleton that acts to reinforce the tumour suppressive actions of TGF-b in the normal prostate epithelial cell. The rationale is that TGF-b induces expression of the actin binding and stabilising proteins transgelin and tropomyosin. Expression of these proteins is progressively repressed during PCa development, and is inhibited by con- stitutive activation of the Ras/MEK/ERK pathway, also known to antagonise TGF-b tumour suppression in PCa. The subsequent de-stabilisation of the actin cytoskeleton might, therefore, result in suppression of TGF-b/Smad signalling as an intact link between cytoskeleton and TGF-b receptor/Smad complex is essential. Filamin A is a scaffold protein that provides this link for receptor associated Smads. It is required for activation of the TGF-b signal transduction pathway. Thus, actin filament disorganisation would prevent Filamin A/R-Smad mediated TGF-b signalling, a subsequent loss of tumour suppression and hence promote the progression of PCa. Furthermore, it could be one mechanism by which the switch to a TGF-b tumourigenic response occurs. Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. Introduction Members of the transforming growth factor beta (TGF-b) super- family are known to modulate cell proliferation, apoptosis, cell dif- ferentiation and cell migration, with TGF-b isoforms 1, 2 and 3 having similar functions [1]. Cytostatic and apoptotic actions of TGF-b in vitro, along with genetic and targeted gene disruption studies of TGF-b 1 and its signalling pathway in vivo, have firmly established it as a tumour suppressor [2,3], at least in the early stages of tumourigenesis. During later stages, TGF-b might act as a tumour promoter, either indirectly by promoting angiogenesis [4], or directly by promoting epithelial to mesenchymal transition and tumour cell invasiveness via perturbed Smad signalling or Smad-independent pathways [5]. Prostate cancer (PCa) is a major public health problem in Western industrialised countries. It is the most commonly diagnosed non-cutaneous cancer and the second leading cause of cancer deaths in industrialised nations [6]. Treatment options re- main limited and have significant drawbacks. Radical prostatecto- my is the most common treatment for organ-confined tumours. It has a 10-year survival rate of 60% but the operation itself carries a 2% mortality rate. In addition, 70% of patients will develop erectile dysfunction, 50% will have urine leakage whilst 2–5% of patients will be incontinent. The most common treatment option for ad- vanced metastatic PCa is to deprive tumours of androgen. This car- ries unwanted side effects of lost libido and potency. Unfortunately for most patients, insensitivity (androgen-independent) to this treatment develops, they relapse and inevitably die from andro- gen-independent metastatic PCa [7]. Associated with progression to androgen insensitivity is a loss of the tumour suppressive properties of TGF-b [8]. Restoration of normal TGF-b activity in PCa cells reduces tumourigenicity [9], and hence TGF-b and its signalling provide an attractive target for therapeutic approaches. How normal TGF-b signalling is main- tained, however, is not fully understood [10]. In this working hypothesis we present an argument for an intimate association between the TGF-b signalling pathway and the actin cytoskeleton that reinforces the tumour suppressive actions of TGF-b in the normal prostate epithelial cell. 0306-9877/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.02.021 ⇑ Corresponding author. Tel.: +61 2 93512514; fax: +61 2 93518400. E-mail address: stephen.assinder@sydney.edu.au (S. Assinder). Medical Hypotheses 76 (2011) 802–804 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy