Forced expression of Wnt antagonists sFRP1 and WIF1 sensitizes chronic myeloid leukemia cells to tyrosine kinase inhibitors

Abstract

Chronic myeloid leukemia is a clonal myeloproliferative disorder that arises from the neoplastic transformation of the hematopoietic stem cell, in which the Wnt/β-catenin signaling pathway has been demonstrated to play an important role in disease progression. However, the role of Wnt signaling antagonists in therapy resistance and disease progression has not been fully investigated. We aimed to study the effects of Wnt/β-catenin pathway antagonists-secreted frizzledrelated protein 1 and Wnt inhibitory factor 1-on resistance toward tyrosine kinase inhibitors in chronic myeloid leukemia. Response to tyrosine kinase inhibitors was analyzed in secreted frizzled-related protein 1 and Wnt inhibitory factor 1 stably transfected K562 cells. Experiments were repeated using a tetracycline-inducible expression system, confirming previous results. In addition, response to tyrosine kinase inhibitor treatment was also analyzed using the secreted frizzled-related protein 1 expressing, BCR-ABL positive MEG01 cell line, in the presence and absence of a secreted frizzled-related protein 1 inhibitor. Our data suggests that total cellular β-catenin levels decrease in the presence of secreted frizzled-related protein 1 and Wnt inhibitory factor 1, and a significant increase in cell death after tyrosine kinase inhibitor treatment is observed. On the contrary, when secreted frizzled-related protein 1 is suppressed, total β-catenin levels increase in the cell and the cells become resistant to tyrosine kinase inhibitors. We suggest that Wnt antagonists carry the potential to be exploited in designing new agents and strategies for the advanced and resistant forms of chronic myeloid leukemia.

Epigenetics of SFRP1: The Dual Roles in Human Cancers

“…However, CML patients with methylated SFRP1 correlated with imatinib therapy resistance as well as additional second Philadelphia chromosome abnormalities [93]. Moreover, expression of antagonists SFRP1 and WIF1 was shown to sensitize chronic myeloid leukemia (CML) cells to tyrosine kinase inhibitors [94]. In in vitro experiments involving K562 cells stably expressing SFRP1, the sensitivity toward imatinib, dasatinib, and nilotinib, were 75%, 43%, and 48% more sensitive, respectively, when compared to empty vector-transfected controls [94].…”

Secreted Wnt antagonists in leukemia: A road yet to be paved

“…In healthy cells β-catenin levels are tightly controlled by secreted and/or intracellular located inhibitory proteins. Epigenetic abnormalities and silencing suppressors of the pathway trigger the increase of β-catenin levels, leading to the uncontrolled activation of the Wnt signaling pathway [26,27].…”

“…Regarding therapeutic interventions, Pehlivan et al showed that induced WIF1 expression will sensitize CML cells to tyrosine kinase inhibitors, again making Wnt signaling a promising target in TKI resistant patients. The WIF1 gene was reported to be hypermethylated in CML cell lines [27]. However, to date there has been no reports on the expression levels and regulatory effect of WIF1 in CML patients.…”

“…Forced sFRP1 expression in CML cell lines will sensitize cells to tyrosine kinase inhibitors. When sFRP1 and WIF1 are forced to re-expressed, they increase the apoptotic susceptibility of the cells in response to tyrosine kinase inhibitors [27].…”

Sfrp1 attenuates TAC-induced cardiac dysfunction by inhibiting Wnt signaling pathway- mediated myocardial apoptosis in mice

“…For instance, it was reported that Sfrp1 was beneficial in recovering cardiac function and structural damage in animal model of myocardial infarction [ 6 ]. Sfrp1 was proved to compete the frizzled receptor of Wnt signaling and further to act as a suppressor of Wnt signaling [ 7 ].…”