title: Upregulation of miR-150* and miR-630 induces apoptosis in pancreatic cancer cells by targeting IGF-1R.
abstract: MicroRNAs have been implicated in many critical cellular processes including apoptosis. We have previously found that apoptosis in pancreatic cancer cells was induced by adamantyl retinoid-related (ARR) molecule 3-Cl-AHPC. Here we report that 3-Cl-AHPC-dependent apoptosis involves regulating a number of microRNAs including miR-150* and miR-630. 3-Cl-AHPC stimulated miR-150* expression and caused decreased expression of c-Myb and IGF-1R in the pancreatic cancer cells. 3-Cl-AHPC-mediated reduction of c-Myb resulted in diminished binding of c-Myb with IGF-1R and Bcl-2 promoters, thereby causing repression of their transcription and protein expression. Over-expression of miR-150* also resulted in diminished levels of c-Myb and Bcl-2 proteins. Furthermore, the addition of the miRNA inhibitor 2'-O-methylated miR-150 blocked 3-Cl-AHPC-mediated increase in miR-150* levels and abrogated loss of c-Myb protein. Knockdown of c-Myb in PANC-1 cells resulted in enhanced apoptosis both in the presence or absence of 3-Cl-AHPC confirming the anti-apoptotic property of c-Myb. Overexpression of miR-630 also induced apoptosis in the pancreatic cancer cells and inhibited target protein IGF-1R mRNA and protein expression. Together these results implicate key roles for miR-150* and miR-630 and their targeting of IGF-1R to promote apoptosis in pancreatic cancer cells.
authors.affiliation: Department of Oncology, Wayne Sate University, Detroit, Michigan, United States of America.
authors.forename: Lulu
authors.initials: L
authors.lastname: Farhana
authors.forename: Marcia I
authors.initials: MI
authors.lastname: Dawson
authors.forename: Farhan
authors.initials: F
authors.lastname: Murshed
authors.forename: Jayanta K
authors.initials: JK
authors.lastname: Das
authors.forename: Arun K
authors.initials: AK
authors.lastname: Rishi
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fontana
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D019254:Genes, bcl-2; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
chemical_list: D000218:Adamantane; D051927:CD24 Antigen; D002934:Cinnamates; D018960:Hyaluronan Receptors; D035683:MicroRNAs; D020598:Proto-Oncogene Proteins c-myb; D017526:Receptor, IGF Type 1; C480030:4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid; C533097:MIR150, human; C548399:MIRN630 microRNA, human