Abstract
Interaction of myeloma cells with osteoclasts (OC) can enhance tumor cell expansion through activation of complex signaling transduction networks. Both cells reside in the bone marrow, a hypoxic niche. How OC-myeloma interaction in a hypoxic environment affects myeloma cell growth and their response to drug treatment is poorly understood. In this study, we i) cultured myeloma cells in the presence/absence of OCs under normoxia and hypoxia conditions and did protein profiling analysis using reverse phase protein array; ii) computationally developed an Integer Linear Programming approach to infer OC-mediated myeloma cell-specific signaling pathways under normoxic and hypoxic conditions. Our modeling analysis indicated that in the presence OCs, (1) cell growth-associated signaling pathways, PI3K/AKT and MEK/ERK, were activated and apoptotic regulatory proteins, BAX and BIM, down-regulated under normoxic condition; (2) β1 Integrin/FAK signaling pathway was activated in myeloma cells under hypoxic condition. Simulation of drug treatment effects by perturbing the inferred cell-specific pathways showed that targeting myeloma cells with the combination of PI3K and integrin inhibitors potentially (1) inhibited cell proliferation by reducing the expression/activation of NF-κB, S6, c-Myc, and c-Jun under normoxic condition; (2) blocked myeloma cell migration and invasion by reducing the expression of FAK and PKC under hypoxic condition.
Highlights
Interaction of myeloma cells with osteoclasts (OC) can enhance tumor cell expansion through activation of complex signaling transduction networks
In order to determine the effect of OCs on myeloma cell growth, RPMI 8226 myeloma cells were cultured in the presence or absence of OCs up to 72 h
We evaluated the effect of hypoxia on myeloma cell growth w/wo OCs
Summary
Interaction of myeloma cells with osteoclasts (OC) can enhance tumor cell expansion through activation of complex signaling transduction networks Both cells reside in the bone marrow, a hypoxic niche. We i) cultured myeloma cells in the presence/absence of OCs under normoxia and hypoxia conditions and did protein profiling analysis using reverse phase protein array; ii) computationally developed an Integer Linear Programming approach to infer OC-mediated myeloma cell-specific signaling pathways under normoxic and hypoxic conditions. Simulation of drug treatment effects by perturbing the inferred cell-specific pathways showed that targeting myeloma cells with the combination of PI3K and integrin inhibitors potentially (1) inhibited cell proliferation by reducing the expression/activation of NF-κB, S6, c-Myc, and c-Jun under normoxic condition; (2) blocked myeloma cell migration and invasion by reducing the expression of FAK and PKC under hypoxic condition. The time-series RPPA data were applied to the generic signaling networks to infer OCs-mediated myeloma-specific pathways
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