A Switch from Canonical to Noncanonical Wnt Signaling Mediates Drug Resistance in Colon Cancer Cells

Abstract

Butyrate, a fermentation product of fiber in the colon, acts as a histone deacetylase inhibitor (HDACi) and induces apoptosis in colon cancer (CC) cells in vitro. We have reported that the apoptotic effects of butyrate are dependent upon the hyperactivation of the Wnt/beta-catenin pathway. However, prolonged exposure of CC cells to increasing concentrations of butyrate results in the acquisition of resistance to the Wnt/beta-catenin- and apoptosis-inducing effects of this agent, as well as cross-resistance to structurally different HDACis. Here we report that one mechanism whereby HDACi resistance arises is through the increase of beta-catenin-independent (noncanonical) Wnt signaling. Compared to HDACi-sensitive HCT-116 CC cells, HDACi-resistant HCT-R cells exhibit higher levels of AKT/PKB cell survival signaling, which is in part induced by WNT5A and its receptor ROR2. The induction of AKT signaling by HDACis is also detected in other CC cell lines, albeit to a lesser extent than in the drug-resistant HCT-R cells. The observations suggested that the apoptotic effect of butyrate and other HDACis in CC cells can be augmented by inhibitors of pAKT. In agreement with the hypothesis, the combination of MK2206, a pAKT inhibitor, and a HDACi (butyrate or LBH589) induced higher apoptosis in CC cells compared to each agent alone. The exposure to both agents also re-sensitized the HCT-R cells to apoptosis. Finally, the concept of simultaneously inducing canonical Wnt activity and suppressing AKT signaling was translated into a combination of diet-derived agents. Diet-derived pAKT inhibitors (caffeic acid phethyl ester, sulforaphane, dilallyl trisulfide) suppressed the butyrate-induced levels of pAKT, and increased the apoptotic effects of butyrate in both drug-sensitive and drug-resistant CC cells.Our findings can be translated into (a) CC therapy employing combinations of synthetic HDACis and inhibitors of pAKT, as well as (b) CC prevention based upon diets that result in sufficient amounts of butyrate and pAKT inhibitors.

WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors

“…We further showed that WNT5A promoted the growth and survival of both naive parental cells and BRAFi-resistant melanoma cells. Previous reports found that high expression of WNT5A similarly results in reduced responsiveness of colon cancer cells to histone deacetylase inhibitors (21) and reduced responsiveness of pancreatic cancer cells to gemcitabine (58). Along with these previous studies, our current work highlights an emerging role for WNT5A-dependent signaling in mediating drug resistance in cancer.…”

“…Recent studies have reported that altered WNT/β-catenin signaling can change the sensitivity of tumor cells to therapeutic drugs (21)(22)(23)(24), yet potential roles for β-catenin-independent WNT signaling in drug resistance are not well understood. In the present study, we found that WNT5A protein and transcript levels were dramatically increased in BRAFi-resistant cell lines and in patient tumors.…”

Sensitization of HER2 Positive Breast Cancer Cells to Lapatinib Using Plants-Derived Isothiocyanates

“…On the other hand, SFN suppressed butyrate-induced Akt phosphorylation in colon cancer HCT-116 line (40) and at 10-40 mM concentrations decreased both total and phosphorylated Akt in SKOV3, C3, and T3 ovarian cancer cell lines (41). SFN also inhibited Akt-mTOR pathway by lowering the protein levels and phosphorylation of Akt and mTOR in pre-B and T-cell acute lymphoblastic leukemia (42).…”

WNT signaling in glioblastoma and therapeutic opportunities

“…100 WNT5A activated Akt signaling and rendered colon cells resistant to histone deacetylase inhibitors. 101 Conversely, inhibition of WNT5A led to increased druginduced apoptosis in pancreatic cancer. 102 In GBM, Auger et al reported that WNT signaling promotes resistance to temozolomide, a standard chemotherapeutic agent for GBM patients.…”