Targeting pro-invasive oncogenes with short chain fatty acid-hexosamine analogues inhibits the mobility of metastatic MDA-MB-231 breast cancer cells.
Per-butanoylated N-acetyl-D-mannosamine (Bu(4)ManNAc), a SCFA-hexosamine cancer drug candidate with activity manifest through intact n-butyrate-carbohydrate linkages, reduced the invasion of metastatic MDA-MB-231 breast cancer cells unlike per-butanoylated-D-mannose (Bu(5)Man), a clinically tested compound that did not alter cell mobility. To gain molecular-level insight, therapeutic targets implicated in metastasis were investigated. The active compound Bu(4)ManNAc reduced both MUC1 expression and MMP-9 activity (via down-regulation of CXCR4 transcription), whereas "inactive" Bu(5)Man had counterbalancing effects on these oncogenes. This divergent impact on transcription was linked to interplay between HDACi activity (held by both Bu(4)ManNAc and Bu(5)Man) and NF-kappaB activity, which was selectively down-regulated by Bu(4)ManNAc. Overall, these results establish a new therapeutic end point (control of invasion) for SCFA-hexosamine hybrid molecules, define relative contributions of molecular players involved in cell mobility and demonstrate that Bu(4)ManNAc breaks the confounding link between beneficial HDACi activity and the simultaneous deleterious activation of NF-kappaB often found in epigenetic drug candidates.
Campbell
Christopher T
CT
Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
Aich
Udayanath
U
Weier
Christopher A
CA
Wang
Jean J
JJ
Choi
Sean S
SS
Wen
Mary M
MM
Maisel
Katharina
K
Sampathkumar
Srinivasa-Gopalan
SG
Yarema
Kevin J
KJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D044127:Epigenesis, Genetic; D005227:Fatty Acids / Q000737:chemistry*; D006595:Hexosamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000235:genetics; D009362:Neoplasm Metastasis; D019718:Receptors, CXCR4 / Q000378:metabolism
D000970:Antineoplastic Agents; C527276:CXCR4 protein, human; D005227:Fatty Acids; D006595:Hexosamines; D016328:NF-kappa B; D019718:Receptors, CXCR4; D020780:Matrix Metalloproteinase 9; C002022:N-acetylmannosamine