title: Mechanisms of neuroblastoma cell growth inhibition by CARP-1 functional mimetics.
abstract: Neuroblastomas (NBs) are a clinically heterogeneous group of extra cranial pediatric tumors. Patients with high-risk, metastatic NBs have a long-term survival rate of below 40%, and are often resistant to current therapeutic modalities. Due to toxic side effects associated with radiation and chemotherapies, development of new agents is warranted to overcome resistance and effectively treat this disease in clinic. CARP-1 functional mimetics (CFMs) are an emerging class of small molecule compounds that inhibit growth of diverse cancer cell types. Here we investigated NB inhibitory potential of CFMs and the molecular mechanisms involved. CFM-1, -4, and -5 inhibited NB cell growth, in vitro, independent of their p53 and MYCN status. CFM-4 and -5 induced apoptosis in NB cells in part by activating pro-apoptotic stress-activated kinases (SAPKs) p38 and JNK, stimulating CARP-1 expression and cleavage of PARP1, while promoting loss of the oncogenes C and N-myc as well as mitotic cyclin B1. Treatments of NB cells with CFM-4 or -5 also resulted in loss of Inhibitory κB (IκB) α and β proteins. Micro-RNA profiling revealed upregulation of XIAP-targeting miR513a-3p in CFM-4-treated NB, mesothelioma, and breast cancer cells. Moreover, exposure of NB and breast cancer cells to CFM-4 or -5 resulted in diminished expression of anti-apoptotic XIAP1, cIAP1, and Survivin proteins. Expression of anti-miR513a-5p or miR513a-5p mimic, however, interfered with or enhanced, respectively, the breast cancer cell growth inhibition by CFM-4. CFMs also impacted biological properties of the NB cells by blocking their abilities to migrate, form colonies in suspension, and invade through the matrix-coated membranes. Our studies indicate anti-NB properties of CFM-4 and 5, and suggest that these CFMs and/or their future analogs have potential as anti-NB agents.
authors.affiliation: John D. Dingell VA Medical Center, Wayne State University, Detroit, Michigan, United States of America; Oncology Department, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Magesh
authors.initials: M
authors.lastname: Muthu
authors.affiliation: John D. Dingell VA Medical Center, Wayne State University, Detroit, Michigan, United States of America; Oncology Department, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Vino T
authors.initials: VT
authors.lastname: Cheriyan
authors.affiliation: John D. Dingell VA Medical Center, Wayne State University, Detroit, Michigan, United States of America; Oncology Department, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Munie
authors.affiliation: John D. Dingell VA Medical Center, Wayne State University, Detroit, Michigan, United States of America; Pathology Department, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Edi
authors.initials: E
authors.lastname: Levi
authors.affiliation: John D. Dingell VA Medical Center, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Frank
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Abdelkader E
authors.initials: AE
authors.lastname: Ashour
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, United States of America.
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
authors.affiliation: John D. Dingell VA Medical Center, Wayne State University, Detroit, Michigan, United States of America; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States of America; Oncology Department, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Rishi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors*; D001570:Benzodiazepinones / Q000494:pharmacology*; D032701:Biomimetics / Q000379:methods; D001943:Breast Neoplasms / Q000188:drug therapy; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D016259:Genes, myc / Q000235:genetics; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C115681:APC2 protein, human; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; D001570:Benzodiazepinones; C477529:CCAR1 protein, human; C119032:CFM 1; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D006131:Growth Inhibitors; D051034:Inhibitor of Apoptosis Proteins; C546275:MIRN513A1 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases