Heme-oxygenase-1 implications in cell morphology and the adhesive behavior of prostate cancer cells

Abstract

Prostate cancer (PCa) is the second leading cause of cancer death in men. Although previous studies in PCa have focused on cell adherens junctions (AJs), key players in metastasis, they have left the molecular mechanisms unexplored. Inflammation and the involvement of reactive oxygen species (ROS) are critical in the regulation of cell adhesion and the integrity of the epithelium. Heme oxygenase-1 (HO-1) counteracts oxidative and inflammatory damage. Here, we investigated whether HO-1 is implicated in the adhesive and morphological properties of tumor cells. Genes differentially regulated by HO-1 were enriched for cell motility and adhesion biological processes. HO-1 induction, increased E-cadherin and β-catenin levels. Immunofluorescence analyses showed a striking remodeling of E-cadherin/β-catenin based AJs under HO-1 modulation. Interestingly, the enhanced levels of E-cadherin and β-catenin coincided with a markedly change in cell morphology. To further our analysis we sought to identify HO-1 binding proteins that might participate in the regulation of cell morphology. A proteomics approach identified Muskelin, as a novel HO-1 partner, strongly implicated in cell morphology regulation. These results define a novel role for HO-1 in modulating the architecture of cell-cell interactions, favoring a less aggressive phenotype and further supporting its anti-tumoral function in PCa.

HO-1/CO system in tumor growth, angiogenesis and metabolism — Targeting HO-1 as an anti-tumor therapy

“…Recently, the additional anti-tumoral effect of HO-1 in PCa cells has been discovered. Gueron et al have shown that pharmacologically induced or genetic overexpression of HO-1 enhances E-cadherin and β-catenin in vitro and in vivo suggesting its direct effect on the adhesive behavior of cells [114]. Moreover, the interaction between HO-1 and muskelin, a specific factor involved in shaping cellular morphology and adhesive properties and their relocation from the cell membrane towards the cell nuclei has been observed after HO-1 induction [114].…”

New Insights into the Role of Podoplanin in Epithelial–Mesenchymal Transition

“…One is the increase in cellular motility driven by podoplanin interacting with the ERM proteins-Rho GTPases axis; the second is what we call "effective cohesiveness" in the cells. Effective cohesiveness designates a sensor mechanism or metabolite that would integrate the overall adhesive properties of a cell, and could be regulated by transcriptional and epigenetic mechanisms, protein stability, presence in the plasma membrane and context-specific mechanisms (like, for instance, the properties of the extracellular matrix) (Adhikary et al, 2014;Boulter et al, 2012;Engl et al, 2014;Friedl et al, 2014;Gueron et al, 2014;Marjoram et al, 2014;McGrail et al, 2014;Murali and Rajalingam, 2014;Orgaz et al, 2014;Sadok and Marshall, 2014;Thiery et al, 2012;50 Zegers and Friedl, 2014). If podoplanin is expressed in a cellular context with low effective cohesiveness, it will promote mesenchymal motility that will end up in EMT.…”

Heme oxygenase-1 in the forefront of a multi-molecular network that governs cell–cell contacts and filopodia-induced zippering in prostate cancer

“…11 Although the role of HO-1 in cancer is controversial, 12 we have shown that its pharmacologic or genetic upregulation is associated with a less aggressive phenotype in PCa. 13 HO-1 inhibits cell proliferation, migration and invasion, 14 it impairs tumor growth and angiogenesis in vivo and downregulates the expression of target genes associated with inflammation. 14, 15 HO-1 is also implicated in the modulation of cellular adhesion in PCa, upregulating E-cadherin and β -catenin expression, and relocating them to the cell membrane, 13 favoring a more epithelial phenotype.…”

“…13 HO-1 inhibits cell proliferation, migration and invasion, 14 it impairs tumor growth and angiogenesis in vivo and downregulates the expression of target genes associated with inflammation. 14, 15 HO-1 is also implicated in the modulation of cellular adhesion in PCa, upregulating E-cadherin and β -catenin expression, and relocating them to the cell membrane, 13 favoring a more epithelial phenotype. However, it is yet unclear which are the HO-1 interactors and how it regulates cytoskeleton organization.…”