Molecular pharmacology of voltage-gated sodium channel expression in metastatic disease: clinical potential of neonatal Nav1.5 in breast cancer.
A variety of ion channels have been detected in cancer cells. In particular, upregulation of voltage-gated sodium channels (VGSCs) has been associated pathophysiologically with several strongly metastatic carcinomas. This review emphasises breast cancer. Inhibiting VGSC activity in a number of independent ways, using the highly selective tetrodotoxin (TTX), gene silencing and a blocking polyclonal antibody, suppressed a range of cellular behaviors, especially directional motility and invasion, integral to the metastatic cascade. Conversely, transfecting a VGSC into a weakly invasive human prostate cancer cell line significantly increased invasiveness. In vivo, also, VGSC expression has been correlated positively with metastatic status. It has been suggested, therefore (i) that VGSC upregulation is an early event in metastatic progression and (ii) that VGSC expression is a 'switch,' necessary and sufficient for engaging cancer cells in a highly invasive state. Importantly, where studied, mainly prostate and breast cancers, the dominant VGSC (Nav1.7 and Nav1.5, respectively) was found to be an embryonic/neonatal splice variant, consistent with the gene expression being "oncofoetal." In breast cancer, the molecular difference between the adult and neonatal isoforms of the VGSC/Nav1.5 is largest (31 base pairs, generating 7 amino acid differences). We propose that neonatal Nav1.5 is a novel marker with significant clinical potential for management of metastatic breast cancer and describe a number of approaches which may enable tumour-specific targeting. These include various small-molecule drugs, small-interfering RNA, monoclonal antibody and natural neurotoxins.
Onkal
Rustem
R
Division of Cell and Molecular Biology, Neuroscience Solutions to Cancer Research Group, Sir Alexander Fleming Building, South Kensington Campus, Imperial College London, London SW7 2AZ, UK.
Djamgoz
Mustafa B A
MB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D016503:Drug Delivery Systems; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009362:Neoplasm Metastasis / Q000503:physiopathology; D011471:Prostatic Neoplasms / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D062554:NAV1.5 Voltage-Gated Sodium Channel; D020033:Protein Isoforms; C568320:SCN5A protein, human; D015222:Sodium Channels