Biochemical constitution of extracellular medium is critical for control of human breast cancer MDA-MB-231 cell motility.
Although voltage-gated sodium channel (VGSC) activity, upregulated significantly in strongly metastatic human breast cancer cells, has been found to potentiate a variety of in vitro metastatic cell behaviors, the mechanism(s) regulating channel expression/activity is not clear. As a step toward identifying possible serum factors that might be responsible for this, we tested whether medium in which fetal bovine serum (FBS) was substituted with a commercial serum replacement agent (SR-2), comprising insulin and bovine serum albumin, would influence the VGSC-dependent in vitro metastatic cell behaviors. Human breast cancer MDA-MB-231 cells were used as a model. Measurements of lateral motility, transverse migration and adhesion showed consistently that the channel's involvement in metastatic cell behaviors depended on the extracellular biochemical conditions. In normal medium (5% FBS), tetrodotoxin (TTX), a highly specific blocker of VGSCs, suppressed these cellular behaviors, as reported before. In contrast, in SR-2 medium, TTX had opposite effects. However, blocking endogenous insulin/insulin-like growth factor receptor signaling with AG1024 eliminated or reversed the anomalous effects of TTX. Insulin added to serum-free medium increased migration, and TTX increased it further. In conclusion, (1) the biochemical constitution of the extracellular medium had a significant impact upon breast cancer cells' in vitro metastatic behaviors and (2) insulin, in particular, controlled the mode of the functional association between cells' VGSC activity and metastatic machinery.
Neuroscience Solutions to Cancer Research Group, Division of Cell and Molecular Biology, Imperial College London, Sir Alexander Fleming Building, South Kensington Campus, London, UK.
Huiyan
H
Pan
Mustafa B A
MB
Djamgoz
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D018613:Microscopy, Confocal; D008954:Models, Biological; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
D003470:Culture Media; D007328:Insulin; D017451:Receptors, Somatomedin; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D020032:Tyrphostins; C447031:tyrphostin AG 1024; D013779:Tetrodotoxin