Disease relevance of IL24

• The melanoma differentiation-associated gene (mda-7; approved gene symbol IL24) is a tumor suppressor gene whose protein expression in normal cells is restricted to the immune system and to melanocytes [1].
• MDA-7/IL24 has been implicated in apoptosis and cellular differentiation in tumor cells and in tumor invasion/metastasis in clinical specimens-properties central to SMC remodeling during proliferative vascular diseases [2].
• Recent studies have shown that mda-7 gene transfer inhibits cell growth and induces apoptosis in melanoma, lung cancer, breast cancer, and other tumor types through activation of various intracellular signaling pathways [1].
• In the current study, we demonstrate that Ad-mda7 transduction of human pancreatic cancer cells results in G2/M cell cycle arrest and cell killing [1].
• In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted IL-24, against human breast cancer cells [3].

High impact information on IL24

• IL-23 induced IL-19 and IL-24 expression in mouse skin, and both genes were also elevated in human psoriasis [4].
• IL-23-dependent epidermal hyperplasia was observed in IL-19(-/-) and IL-24(-/-) mice, but was inhibited in IL-20R2(-/-) mice [4].
• Infection of this CRCA (designated Ad.PEG-E1A-mda-7) in normal mammary epithelial cells and breast cancer cells confirmed cancer cell selective adenoviral replication, mda-7/IL-24 expression, growth inhibition, and apoptosis induction [5].
• Subtraction hybridization identified melanoma differentiation-associated gene-7 (mda-7) as a gene induced during terminal differentiation in human melanoma cells [6].
• Administration of mda-7/IL-24 by means of a replication-incompetent adenovirus (Ad.mda-7) induces apoptosis selectively in diverse human cancer cells without inducing harmful effects in normal fibroblast or epithelial cells [6].

Chemical compound and disease context of IL24

• Enhancement of adenoviral MDA-7-mediated cell killing in human lung cancer cells by geldanamycin and its 17-allyl- amino-17-demethoxy analogue [7].
• After injection of 0.1 mmol per kilogram of body weight of gadopentetate dimeglumine, first-pass MR images were obtained by using an inversion-recovery true-FISP sequence at rest and during infusion of adenosine (140 microg/kg/min) [8].
• The tumor thrombus enhanced intensely on early post gadolinium images and was also well shown on true FISP (Fast Imaging with Steady State Precession) images [9].
• The 3-D FISP technique accurately defined the luminal contours of vessels, allowing precise depiction of vessel stenosis (i.e., renal artery stenosis or common iliac artery stenosis) and clear demonstration of relationship of aortic branch vessels (i.e., renal arteries) to underlying aortic pathology (i.e., aortic aneurysm or dissection) [10].
• Synergistic tumoricidal effect between celecoxib and adenoviral-mediated delivery of mda-7 in human breast cancer cells [11].

Biological context of IL24

• COS cells transfected with either IL-24 receptor heterodimers bind the ligand with similar saturation kinetics [12].
• MDA-7 induces dose-dependent cell death in melanoma tumor cells [13].
• In normal cells, MDA-7 can bind to its cognate receptors and induce phosphorylation of STAT3, without cytotoxic sequelae [13].
• We completed a Phase I dose-escalation clinical trial, in which a nonreplicating adenoviral construct expressing the mda-7 transgene (INGN 241; Ad-mda7) was administered intratumorally to 22 patients with advanced cancer [14].
• Here, we correlate the kinetics of IL-24 mRNA and protein expression in human peripheral blood mononuclear cells (PBMC) stimulated by polyclonal activators phytohemagglutinin (PHA) and lipopolysaccharide (LPS) or by allogeneic major histocompatibility complex [15].

Anatomical context of IL24

• In this study, we evaluated the effects of overexpressing MDA-7/IL24 in various SMC: the apparently "normal" rat PAC1 cell line, primary human coronary artery SMC, and normal rat aortic SMC [2].
• IL-19 and IL-24 also exhibited growth inhibition on a cell line endogenously expressing all three receptor subunits, an effect that was seen at cytokine levels two orders of magnitude above those required for STAT activation or proliferation [16].
• IL-24 (melanoma differentiation-associated gene 7) expression was restricted to monocytes and T cells [17].
• IL-24 binding to either its endogenous receptors on human keratinocytes or to ectopically expressed receptors on baby hamster kidney cells leads to activation of the signal transducers and activators of transcription [12].
• Although mda-7 has been designated as IL-24 based on its gene location in the IL-10 locus and its mRNA expression in leukocytes, no functional evidence supporting this cytokine designation exists [18].

Associations of IL24 with chemical compounds

• When LPS- or PHA-stimulated cells were treated with Actinomycin D, IL-24 mRNA persisted at high levels over the 4-h course of treatment [15].
• Additionally, radiation augments apoptosis induction by mda-7/IL-24 in parental and neomycin-resistant prostate tumor cells [19].
• Treatment with 2-aminopurine (2-AP), a serine/threonine kinase inhibitor, inhibits PKR activation, eIF2alpha phosphorylation, and apoptosis induction by Ad-mda7 [20].
• We show that induction of terminal differentiation of HO-1 cells with IFN-beta+MEZ dramatically increases the half-life of mda-7 mRNA while treatment with cycloheximide results in detectable mda-7 mRNA in control and inducer treated cells [21].
• PURPOSE: To compare the accuracy of multisection true fast imaging with steady-state precession (FISP) with gadolinium-enhanced magnetic resonance (MR) angiography for the detection of coronary artery bypass graft patency [22].

Enzymatic interactions of IL24

• Cytoplasmic MDA-7 with deleted signal sequence was as effective as full-length MDA-7 in potentiating TNF-induced NF-kappaB reporter activity [23].

Regulatory relationships of IL24

• In pancreatic tumor cells, exogenous MDA-7 protein activates STAT3 and kills cells via engagement of IL-20 receptors [1].
• MDA-7 protein induces phosphorylation and nuclear translocation of STAT3 in melanoma cells via both type 1 and type 2 IL-20R [13].
• Mda-7/IL-24 induces apoptosis of diverse cancer cell lines through JAK/STAT-independent pathways [24].
• The second goal was to determine whether iNOS expression could be regulated by MDA-7 expression in melanoma cells [25].
• Upon binding to its receptors, IL-24 induces rapid activation of Stat-1 and Stat-3 transcription factors, which appear to play a role in cell survival and proliferation [26].

Other interactions of IL24

• Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types [27].
• However, the biological effects of these three cytokines appear quite distinct: immune activity with IL-19, skin biology with IL-20, and tumor apoptosis with IL-24 [16].
• Taken together, these results provide compelling evidence for IL-24 being the fourth member of IL-10 family of cytokines to which their specific receptors have been identified [12].
• This study defines a tumor-selective cytotoxic bystander role for secreted MDA-7 protein and identifies a novel receptor-mediated, STAT3-independent, and PKR-independent death pathway [13].
• These molecularly defined N-glycosylated IL-24 dimers elicited dose-dependent secretion of tumor necrosis factor-alpha (TNF-alpha) and IL-6 from human monocytes, as well as cytotoxicity to human melanoma cell lines [28].

Analytical, diagnostic and therapeutic context of IL24

• Phase II trials evaluating the efficacy of mda-7-based gene therapy are warranted [29].
• Expression of MDA-7 and iNOS proteins were evaluated by immunohistochemistry in a total of 81 tumor samples: 38 primary melanomas and 43 metastatic melanomas [25].
• Additionally, recent clinical trials confirm safety and document significant clinical activity of mda-7/IL-24 in patients with diverse solid cancers and melanomas [30].
• A notable property of MDA-7/IL-24 is its ability to induce apoptosis in a large spectrum of human cancer derived cell lines, in mouse xenografts and upon intratumoral injection in human tumors (phase I clinical trials) [31].
• Radiation hybrid mapping assigned the mda-7 gene to human chromosome 1q, at 1q 32.2 to 1q41, an area containing a cluster of genes associated with the IL-10 family of cytokines [32].

References