Transit of hormonal and EGF receptor-dependent signals through cholesterol-rich membranes

Abstract

The functional consequences of changes in membrane lipid composition that coincide with malignant growth are poorly understood. Sufficient data have been acquired from studies of lipid binding proteins, post-translational modifications of signaling proteins, and biochemical inhibition of lipidogenic pathways to indicate that growth and survival pathways might be substantially re-directed by alterations in the lipid content of membranes. Cholesterol and glycosphingolipids segregate into membrane patches that exhibit a liquid-ordered state in comparison to membrane domains containing relatively lower amounts of these classes of lipids. These "lipid raft" structures, which may vary in size and stability in different cell types, both accumulate and exclude signaling proteins and have been implicated in signal transduction through a number of cancer-relevant pathways. In prostate cancer cells, signaling from epidermal growth factor receptor (EGFR) to the serine-threonine kinase Akt1, as well as from IL-6 to STAT3, have been demonstrated to be influenced by experimental interventions that target cholesterol homeostasis. The recent finding that classical steroid hormone receptors also reside in these microdomains, and thus may function within these structures in a signaling capacity independent of their role as nuclear factors, suggests a novel means of cross-talk between receptor tyrosine kinase-derived and steroidogenic signals. Potential points of intersection between components of the EGFR family of receptor tyrosine kinases and androgen receptor signaling pathways, which may be sensitive to disruptions in cholesterol metabolism, are discussed. Understanding the manner in which these pathways converge within cholesterol-rich membranes may present new avenues for therapeutic intervention in hormone-dependent cancers. Cholesterol and CancerExtracellular signals influencing a tumor cell must cross a lipid barrier that is still poorly understood in terms of structure and regulatory function. This brief review focuses on the hypothesis that membrane cholesterol, through its capacity to mediate changes in lipid membrane structure, influences signal transduction mechanisms related to oncogenesis. Here, we specifically explore the concept that membrane cholesterol is a facilitator of cross-talk Correspondence to: Michael R. Freeman, PhD, Children's Hospital Boston, Enders Research Laboratories, suite 1161, 300 Longwood Ave., Boston, MA 02115, Tel: 617-919-2644, Fax: 617-730-0238, E-mail: michael.freeman@childrens.harvard.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. N...

Oxidative stress induces lipid-raft-mediated activation of Src homology 2 domain-containing protein-tyrosine phosphatase 2 in astrocytes

“…Lipid rafts contain several types of signaling molecules and function as platforms for mediating a range of cellular events, including signal transduction, vesicular trafficking, and bacterial/viral entry/infection [24][25][26]. A number of studies show that hormones, bacteria, viruses, and various receptors, such as CD95, CD40, EGFR, and TNFR, exert their biological effects through lipid rafts [27,28]. Oxidative stress induced by ROS is another stimulus that activates several signaling events via lipid rafts [29,30].…”

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

“…Important growth-signaling complexes for pathways such as TGFb, EGFR/MAPK/ERK, AKT, and the AR reside within cholesterol-rich microdomains referred to as lipid rafts whose signaling integrity can be modulated by changes in cellular cholesterol levels that affect membrane fluidity, transport, and protein complex assembly and stability Freeman et al, 2007;Montero et al, 2008). Elevated mitochondrial cholesterol associated with different cancers has also been demonstrated to impair the BAX-mediated apoptotic permeability pore associated with apoptosis and provide an apoptotic escape mechanism (Zhuang et al, 2005;Li et al, 2006Li et al, , 2008MartinezAbundis et al, 2007;Oh et al, 2007;Christenson et al, 2008).…”

“…However, there is also a separate recognition that elevated intracellular cholesterol in non-hormone-dependent tumor cells can contribute to progression based on numerous reports of interference with multiple pathways of growth signaling and apoptosis (Zhuang et al, 2005;Li et al, 2006;Swinnen et al, 2006;Adam et al, 2007;Freeman et al, 2007;Martinez-Abundis et al, 2007;Oh et al, 2007;Christenson et al, 2008;Patra, 2008). The link between intracellular cholesterol and tumor progression has been found in hepatocellular carcinoma, colon, breast, head and neck, and melanoma cancers, either with tumor specimens and/or studies in cancer cell lines (Schabath et al, 2006;Baruthio et al, 2008;Montero et al, 2008).…”

Androgen receptor regulation of the seladin-1/DHCR24 gene: altered expression in prostate cancer

“…In particular, expansion of the cholesterol-rich membrane compartment, within certain limits, is likely to promote the formation of raft-resident signalling complexes that promote cell proliferation and survival in tumoral cells, including CaP. 29 Whereas an association between decreased levels of seladin-1/DHCR24 and metastasis incidence has been found, 5 no evidence concerning the expression of this gene in CaP tissues vs adjacent normal tissues was available, so far. Therefore, we evaluated the amount of seladin-1/DHCR24 mRNA in specimens consecutively collected at surgery from a cohort of 61 patients diagnosed for a clinically localized CaP.…”