Downregulation of DKK-1 and Upregulation of β-Catenin in Cancer Floating Spheroids is Associated with Chemoresistance to Wnt Signaling Pathway Inhibitors
Objectives: DKK-1, a negative regulator of β-catenin in the Wnt pathway is commonly upregulated in cancer cells but its expression and association to chemoresistance have not been investigated extensively. Our aim was to evaluate the expression of DKK-1 and β-catenin as well as the effect of the Wnt pathway modulators iCRT-14 (iCRT) and WAY626611 (WAY) alone or in combination with Nigericin (NIG) on the viability of cancer cells grown under routine conditions (RC) or as floating spheroids (FSs).
Methods: RC or FSs from human prostate (PC3 and LnCAP) and breast (MCF-7 and MDA-MB231) cells were treated for 72 hs with WAY or iCRT. Cell viability was determined by the MTT or the CCK-8 assays and protein expression was determined by western blot analysis.
Results: DKK-1 was expressed at different basal levels in RC but was undetectable in FSs. β-catenin expression was increased in FSs. RC of PC3 and MCF-7 were sensitive to both iCRT and WAY but FSs generated from these cell lines were resistant to both drugs. NIG potentiated the effect of both Wnt inhibitors in FSs.
Conclusion: Marked changes in the expression of Wnt pathway proteins, DKK-1 and β-catenin in FSs are associated with resistance to WAY and iCRT.
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