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: Lulu Farhana, Marcia I Dawson, Farhan Murshed, Jayanta K Das, Arun K Rishi, Joseph A Fontana
• Journal: PloS one (PLoS One) Vol. 8 Issue 5 Pg. e61015 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23675407 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid
• CD24 Antigen
• Cinnamates
• Hyaluronan Receptors
• MIRN150 microRNA, human
• MIRN630 microRNA, human
• MicroRNAs
• Proto-Oncogene Proteins c-myb
• Receptor, IGF Type 1
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology)
• Apoptosis (genetics)
• CD24 Antigen (metabolism)
• Cell Line, Tumor
• Cinnamates (pharmacology)
• Gene Expression
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Genes, bcl-2
• Humans
• Hyaluronan Receptors (metabolism)
• MicroRNAs (genetics, metabolism)
• Neoplastic Stem Cells (metabolism)
• Pancreatic Neoplasms (genetics, metabolism)
• Promoter Regions, Genetic
• Protein Binding
• Proto-Oncogene Proteins c-myb (genetics, metabolism)
• Receptor, IGF Type 1 (genetics, metabolism)
• Spheroids, Cellular
• Tumor Cells, Cultured