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.
Keywords: Multiple myeloma, IL-6, cell proliferation, gene expression, epigenetics, methylation, therapeutic implications, tumor suppressor genes, DNA methylation, chemotherapeutic, anti-IL-6, KAS6/1
Medicinal Chemistry
Title: Targeting the IL-6 Pathway in Multiple Myeloma and its Implications in Cancer-Associated Gene Hypermethylation
Volume: 7 Issue: 5
Author(s): Susan Blaydes Ingersoll, Sarfraz Ahmad, Natalie D. Thoni, Farhana H. Ahmed, Kimberly A. Monahan and John R. Edwards
Affiliation:
Keywords: Multiple myeloma, IL-6, cell proliferation, gene expression, epigenetics, methylation, therapeutic implications, tumor suppressor genes, DNA methylation, chemotherapeutic, anti-IL-6, KAS6/1
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.
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Cite this article as:
Blaydes Ingersoll Susan, Ahmad Sarfraz, D. Thoni Natalie, H. Ahmed Farhana, A. Monahan Kimberly and R. Edwards John, Targeting the IL-6 Pathway in Multiple Myeloma and its Implications in Cancer-Associated Gene Hypermethylation, Medicinal Chemistry 2011; 7 (5) . https://dx.doi.org/10.2174/157340611796799159
DOI https://dx.doi.org/10.2174/157340611796799159 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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