Abstract:
: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 kappa B (NF-kappa B) pathways. 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-kappa B 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.
journal_name
Bloodjournal_title
Bloodauthors
Hu L,Shi Y,Hsu JH,Gera J,Van Ness B,Lichtenstein Adoi
10.1182/blood-2002-08-2640subject
Has Abstractpub_date
2003-04-15 00:00:00pages
3126-35issue
8eissn
0006-4971issn
1528-0020pii
2002-08-2640journal_volume
101pub_type
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