TY - JOUR
T1 - Downstream effectors of oncogenic ras in multiple myeloma cells
AU - Hu, Liping
AU - Shi, Yijiang
AU - Hsu, Jung hsin
AU - Gera, Joseph
AU - Van Ness, Brian
AU - Lichtenstein, Alan
PY - 2003/4/15
Y1 - 2003/4/15
N2 - Ectopic expression of mutated K-ras or N-ras in the interleukin 6 (IL-6)-dependent ANBL6 multiple myeloma cell line induces cytokine-independent growth. To investigate the signaling pathways activated by oncogenic ras that may stimulate IL-6-independent growth, we compared ANBL6 cells stably transfected with mutated K or N-ras genes with wild-type ras-expressing control cells identically transfected with an empty vector. Upon depletion of IL-6, both mutated ras-containing myeloma lines demonstrated constitutive activation of mitogen-activated extracellular kinase 2(MEK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol-3 kinase (PI3-kinase)/AKT, mammalian target of rapamycin (mTOR)/p70S6-kinase, and nuclear factor kappaB (NF-kB) pathway. In contrast, signal transducer and activator of transcription-3 (STAT-3) was not constitutively tyrosine phosphorylated in mutant ras-expressing cells. We used several maneuvers in attempts to selectively target these constitutively active pathways. The mTOR inhibitors rapamycin and CCI-779, the PI3-kinase inhibitor LY294002, and the MEK inhibitor PD98059 all significantly curtailed growth of mutant ras-containing cells. Farnesyl transferase inhibitors, used to target ras itself, had modest effects only against mutant N-ras-containing cells. Growth of mutant N-ras-containing myeloma cells was also inhibited by acute expression of the IKB superrepressor gene, which abrogated NF-kB activation. These results indicate that several pathways contributing to stimulation of cytokine-independent growth are activated downstream of oncogenic ras in myeloma cells. They also suggest that therapeutic strategies that target these pathways may be particularly efficacious in patients whose myeloma clones contain ras mutations.
AB - Ectopic expression of mutated K-ras or N-ras in the interleukin 6 (IL-6)-dependent ANBL6 multiple myeloma cell line induces cytokine-independent growth. To investigate the signaling pathways activated by oncogenic ras that may stimulate IL-6-independent growth, we compared ANBL6 cells stably transfected with mutated K or N-ras genes with wild-type ras-expressing control cells identically transfected with an empty vector. Upon depletion of IL-6, both mutated ras-containing myeloma lines demonstrated constitutive activation of mitogen-activated extracellular kinase 2(MEK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol-3 kinase (PI3-kinase)/AKT, mammalian target of rapamycin (mTOR)/p70S6-kinase, and nuclear factor kappaB (NF-kB) pathway. In contrast, signal transducer and activator of transcription-3 (STAT-3) was not constitutively tyrosine phosphorylated in mutant ras-expressing cells. We used several maneuvers in attempts to selectively target these constitutively active pathways. The mTOR inhibitors rapamycin and CCI-779, the PI3-kinase inhibitor LY294002, and the MEK inhibitor PD98059 all significantly curtailed growth of mutant ras-containing cells. Farnesyl transferase inhibitors, used to target ras itself, had modest effects only against mutant N-ras-containing cells. Growth of mutant N-ras-containing myeloma cells was also inhibited by acute expression of the IKB superrepressor gene, which abrogated NF-kB activation. These results indicate that several pathways contributing to stimulation of cytokine-independent growth are activated downstream of oncogenic ras in myeloma cells. They also suggest that therapeutic strategies that target these pathways may be particularly efficacious in patients whose myeloma clones contain ras mutations.
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U2 - 10.1182/blood-2002-08-2640
DO - 10.1182/blood-2002-08-2640
M3 - Article
C2 - 12515720
AN - SCOPUS:0038281345
SN - 0006-4971
VL - 101
SP - 3126
EP - 3135
JO - Blood
JF - Blood
IS - 8
ER -