title: Targeting the IL-6 pathway in multiple myeloma and its implications in cancer-associated gene hypermethylation.
abstract: Aberrant methylation of tumor suppressor genes (TSG) is an important epigenetic event in cancer, including multiple myeloma (MM). Interleukin-6 (IL-6), which plays a significant role in the pathogenesis of MM, also regulates DNA methylation. However, attempts to bring IL-6 blockade to the clinic have had limited success. We hypothesize that IL-6 regulation of hypermethylation may be an important pathway leading to rational chemotherapeutic/anti-IL-6 combinations. We first studied the correlation of IL-6 expression and dependence in MM cell lines: U266B1, RPMI8226, and KAS6/1. We confirmed that KAS6/1 is IL-6-dependent whereas U266B1 and RPMI8226 cells are IL-6-independent and that blocking IL-6 inhibited the growth of U266B1 (36% inhibition; p<0.05) and KAS6/1 (68% inhibition; p<0.01), but not the RPMI8226 cells. Using RT-PCR, we showed that U266B1 cells express IL-6, but RPMI8226 and KAS6/1 cells do not. This IL-6 expression pattern correlates with the anti-IL-6 inhibition findings. To correlate IL-6 sensitivity with hypermethylation of TSG, we investigated promoter methylation of CDH1 and DcR1. We found that the promoter of DcR1 and CDH1 is methylated in U266B1 cells and un-methylated in RPMI8226 cells. Furthermore, the DcR1 promoter was un-methylated in KAS6/1 cells. These data support our hypothesis that an IL-6-dependent pathway may regulate hypermethylation of TSG in MM. Newer chemotherapeutic agents that affect methylation are being studied in combination with IL-6 blockade.
authors.affiliation: Principal Scientist, Florida Hospital Cancer Institute, Clinical Assistant Professor, Florida State University, 2501 N. Orange Ave., Suite 800, Orlando, FL 32804, USA. susan.blaydes@flhosp.org.
authors.forename: Susan Blaydes
authors.initials: SB
authors.lastname: Ingersoll
authors.forename: Sarfraz
authors.initials: S
authors.lastname: Ahmad
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Thoni
authors.forename: Farhana H
authors.initials: FH
authors.lastname: Ahmed
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Monahan
authors.forename: John R
authors.initials: JR
authors.lastname: Edwards
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D000093242:Interleukin-6 Inhibitors
chemical_list: D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors