Interaction of Endocannabinoid System and Steroid Hormones in the Control of Colon Cancer Cell Growth

Department of Pharmaceutical Sciences, University of Salerno, Fisciano, SA, Italy.
Journal of Cellular Physiology (Impact Factor: 3.84). 01/2012; 227(1):250-8. DOI: 10.1002/jcp.22727
Source: PubMed


Increasing evidence suggest the role of the cannabinoid receptors (CBs) in the control of cell survival or death and signaling pathways involved in tumor progression. Cancer cell lines are characterized by a subtle modulation of CB levels which produces a modified responsiveness to specific ligands, but the molecular mechanisms underlying these events are poorly and partially understood. We previously provided evidence that the endocannabinoid (EC) anandamide (AEA) exerts anti-proliferative effect likely by modulation of the expression of genes involved in the cellular fate. In this study we focused on the role of the CB1 receptor, ECs, and steroids in the mechanisms involved in colorectal cancer (CRC) cell growth inhibition in vitro. We demonstrated that, in DLD1 and SW620 cells, 17β-estradiol induced a specific and strong up-regulation of the CB1 receptor by triggering activation of the CB1 promoting region, localized at the exon 1 of the CNR1 gene. Moreover, treatment of DLD1 and SW620 cells with Met-F-AEA, a stable AEA-analogous, or URB597, a selective inhibitor of FAAH, induced up-regulation of CB1 expression by co-localization of PPARγ and RXRα at the promoting region. Finally, increased availability of AEA, of both exogenous and endogenous sources, induced the expression of estrogen receptor-beta in both cell lines. Our results partially elucidated the role of EC system in the molecular mechanisms enrolled by steroids in the inhibition of colon cancer cell growth and strongly suggested that targeting the EC system could represent a promising tool to improve the efficacy of CRC treatments.

Download full-text


Available from: Simona Pisanti
  • Source
    • "In human glioma tissues, increased expression of cannabinoid receptors (CB1 and CB2) has been reported to correlate with higher tumor grades [133]; but this remains controversial [134], [135], [136]. In other tumors, a role of CNR1 in invasion and metastasis has been reported [137], [138] and the endocanabinoid system has been reported as a promising tool to improve the efficacy of steroids in colon cancer [139]. Globally, the cannabinoid system appears to present anti-proliferative, anti-angiogenic and pro-apoptotic properties. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastomas (GBMs) are highly aggressive, invasive brain tumors with bad prognosis and unmet medical need. These tumors are heterogeneous being constituted by a variety of cells in different states of differentiation. Among these, cells endowed with stem properties, tumor initiating/propagating properties and particularly resistant to chemo- and radiotherapies are designed as the real culprits for tumor maintenance and relapse after treatment. These cells, termed cancer stem-like cells, have been designed as prominent targets for new and more efficient cancer therapies. G-protein coupled receptors (GPCRs), a family of membrane receptors, play a prominent role in cell signaling, cell communication and crosstalk with the microenvironment. Their role in cancer has been highlighted but remains largely unexplored. Here, we report a descriptive study of the differential expression of the endo-GPCR repertoire in human glioblastoma cancer stem-like cells (GSCs), U-87 MG cells, human astrocytes and fetal neural stem cells (f-NSCs). The endo-GPCR transcriptome has been studied using Taqman Low Density Arrays. Of the 356 GPCRs investigated, 138 were retained for comparative studies between the different cell types. At the transcriptomic level, eight GPCRs were specifically expressed/overexpressed in GSCs. Seventeen GPCRs appeared specifically expressed in cells with stem properties (GSCs and f-NSCs). Results of GPCR expression at the protein level using mass spectrometry and proteomic analysis are also presented. The comparative GPCR expression study presented here gives clues for new pathways specifically used by GSCs and unveils novel potential therapeutic targets.
    Full-text · Article · Mar 2014 · PLoS ONE
  • Source
    • "Thus, new strategies to overcome chemotherapeutic resistance are under exploration and there is the need to design new drugs for a more selective tumor therapy. Strong evidence suggests that the endogenous cannabinoid system, comprising cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and degradation, may provide new targets for tumor intervention (Malfitano et al., 2011) and elucidated the potential role of endocannabinoids in the control of CRC growth and progression (Proto et al., 2012; Izzo et al., 2008). Endocannabinoid levels are strongly elevated in colorectal adenomatous polyps but slightly reduced in carcinomas Contents lists available at ScienceDirect journal homepage: "
    [Show abstract] [Hide abstract]
    ABSTRACT: An emerging new class of targeted therapeutic molecules against the enzyme fatty acid amide hydrolase (FAAH) is a novel series of pyrrolo-1,5-benzoxa(thia)zepine compounds. A member of this family, pyrrolo-1,5-benzoxazepine-15 (PBOX-15), is a tubulin depolymerizing agent displaying a proapoptotic activity in a variety of human tumor cell types, including those derived from both solid and hematological malignancies, with minimal toxicity towards normal blood and bone marrow cells. In this study, we evaluated the PBOX-15-mediated effects in human colorectal cancer cell (CRC) lines. The compound, used at doses equal to or greater than 1μM inhibits the proliferation of human CRC cell lines in a dose- and time-dependent manner, inducing a significant cell cycle arrest in the G2/M phase. DNA fragmentation assays and western blot analysis demonstrated that treatments prolonged over 48hours triggered a strong activation of the intrinsic apoptotic pathway as indicated by activation of caspase-3, caspase-9 and PARP. Moreover, nanomolar doses of PBOX-15, unable to cause microtubule depolymerisation, significantly improved the oxaliplatin and 5-fluouracil -induced anti-proliferative effects in CRC cell lines. These results showed, for the first time, that PBOX-15 represents a promising compound for the treatment of human CRC and a strong candidate for novel therapeutic options.
    Full-text · Article · Jul 2013 · European journal of pharmacology
  • Source
    • "CB1 is preferentially expressed in the central nervous system (CNS), [3], [4], [5] CB2 is predominantly expressed by immune cells [6], however evidence demonstrated its presence in the CNS [7], [8], [9]. Increasing reports suggest a role of the endocannabinoid system in a variety of physiological and pathophysiological conditions, including immunomodulation, [10] pain, cancer, [11], [12], [13], [14] psychiatric disorders [15] and immune-mediated diseases of the CNS such as multiple sclerosis (MS) [16]. In particular, MS results in focal areas of inflammation containing immune cell infiltrates and demyelination, [17] the prevailing view is that CD4+ T cells initiate the disease producing pro-inflammatory cytokines that drive the inflammatory process. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The efficacy of cannabinoids in the treatment of multiple sclerosis is widely documented; however their use is limited by psychoactivity mainly ascribed to the activation of the cannabinoid receptor CB1. Emerging findings support as alternative strategy in the treatment of neurodegenerative disorders, the application of compounds targeting the CB2 receptor, since likely unrelated to these side effects. Recently, a novel class of compounds, 1,8-naphthyridine, pyridine and quinoline derivatives have been demonstrated to show high CB2 receptor selectivity and affinity versus the CB1 receptor. Considering that the CB2 receptor is mainly expressed in cell and organs of the immune system, in this study we assessed the potential immune-modulatory effects of these compounds in activated lymphocytes isolated from MS patients with respect to healthy controls. These compounds blocked cell proliferation through a mechanism partially ascribed to the CB2 receptor, down-regulated TNF-α production and did not induce cell death. They also down-regulated Akt, Erk and NF-kB phosphorylation. Despite comparable effects observed in patients and healthy controls, these compounds, in particular, 1,8-naphthyridine and quinoline derivatives inhibited cell activation markers in MS patient derived lymphocytes more efficiently than in healthy control derived cells. Indeed, 1,8-naphthyridin-2-one derivative reduced the levels of Cox-2 in lymphocytes from patients whereas no effect was observed in control cells. Our findings suggest potential application of these drugs in neuro-inflammation, supporting further investigations of the effects of compounds in the therapy of MS, particularly on the aspects regarding activation and inflammation.
    Full-text · Article · May 2013 · PLoS ONE
Show more