Activation of N-ras and K-ras induced by interleukin-6 in a myeloma cell line: implications for disease progression and therapeutic response.
Ras is a major signaling molecule activated by interleukin-6. There have been no published reports, however, that specifically examine the kinetics and percentage of Ras activation in response to IL-6. Model cell lines were used to study activation of N- and K-ras induced by IL-6. All of the myeloma cell lines we tested express both N-ras and K-ras, but not H-ras. GTP-bound Ras was measured and the percentage of the total Ras pool that was activated in response to IL-6 was calculated. IL-6 is able to transiently activate both N- and K-ras in the ANBL6 cell line. In addition, increasing concentrations of IL-6 are able to activate increasing levels of both N- and K-ras. One ng/ml of IL-6 is able to activate approximately 10% of the N-ras pool and 18% of the K-ras pool. The amount of Ras-GTP in the cells correlates with the level of proliferation at low levels, but proliferation plateaus when higher levels of Ras-GTP are present. Protection from dexamethasone-induced apoptosis correlates with IL-6 concentration and Ras activation. However, IL-6 enhances apoptosis induced by doxorubicin. Interestingly, the ANBL6 cell line transfected with an N-ras12 or a K-ras12 gene is protected from doxorubicin-induced apoptosis.
Rowley
Matt
M
Graduate Program in Molecular, Cellular, Developmental Biology and Genetics, The University of Minnesota, Minneapolis, Minnesota, MN 55455, USA.
Van Ness
Brian
B
D017209:Apoptosis / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D011905:Genes, ras; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology* / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured
D015850:Interleukin-6; D003907:Dexamethasone; D004317:Doxorubicin