Targeting the IL-6 Pathway in Multiple Myeloma and its Implications in Cancer-Associated Gene Hypermethylation

Author(s): Susan Blaydes Ingersoll , Sarfraz Ahmad , Natalie D. Thoni , Farhana H. Ahmed , Kimberly A. Monahan , John R. Edwards .

Journal Name: Medicinal Chemistry

Volume 7 , Issue 5 , 2011

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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

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Article Details

VOLUME: 7
ISSUE: 5
Year: 2011
Page: [473 - 479]
Pages: 7
DOI: 10.2174/157340611796799159
Price: $58

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