WNT7A/β-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer

Abstract

We previously characterized the link between WNT7A and the progression of ovarian cancer. Other groups have identified FGF1 as a relevant risk factor in ovarian cancer. Here, we show a linkage between these two signaling pathways that may be exploited to improve treatment and prognosis of patients with ovarian cancer. High expression of WNT7A and FGF1 are correlated in ovarian carcinomas and poor overall patient survival. A chromatin immunoprecipitation assay demonstrated that WNT7A/β-catenin signaling directly regulates FGF1 expression via TCF binding elements in the FGF1-1C promoter locus. In vitro gene manipulation studies revealed that FGF1 is sufficient to drive the tumor promoting effects of WNT7A. In vivo xenograft studies confirmed that the stable overexpression of WNT7A or FGF1 induced a significant increase in tumor incidence, while FGF1 knockdown in WNT7A overexpressing cells caused a significant reduction in tumor size. Niclosamide most efficiently abrogated WNT7A/β-catenin signaling in our model, inhibited β-catenin transcriptional activity and cell viability, and increased cell death. Furthermore, niclosamide decreased cell migration following an increase in E-cadherin subsequent to decreased levels of SLUG. The effects of niclosamide on cell functions were more potent in WNT7A overexpressing cells. Oral niclosamide inhibited tumor growth and progression in an intraperitoneal xenograft mouse model representative of human ovarian cancer. Collectively, these results indicate that FGF1 is a direct downstream target of WNT7A/β-catenin signaling and this pathway has potential as a therapeutic target in ovarian cancer. Moreover, niclosamide is a promising inhibitor of this pathway and may have clinical relevance.

JAK2/STAT3 pathway as a therapeutic target in ovarian cancers

“…Additionally, oral niclosamide inhibited tumor growth and progression in an intraperitoneal xenograft mouse model representative of human ovarian cancer without significant side effects (20). Recently, niclosamide has been shown to inhibit several pathways including NF-κB, Notch, ROS, mTORC1, and Wnt/β-catenin pathway (16,(21)(22)(23)(24)(25). So there might be several mechanisms of anti-neoplastic activity in niclosamide other than inhibition of JAK2/STAT3 pathway.…”

Altering the Proteoglycan State of Transforming Growth Factor β Type III Receptor (TβRIII)/Betaglycan Modulates Canonical Wnt/β-Catenin Signaling

“…Wnt glycoproteins regulate three distinct Wnt signaling pathways to mediate cell fate, proliferation, and apoptosis as well as cancer initiation and progression in multiple cancers, including ovarian (1)(2)(3)(4)(5)(6)(7)(8)(9). Activation of the canonical Wnt/␤-catenin pathway begins with the binding of Wnt to its cell surface receptors, Frizzled and LDL receptor-related proteins 5/6 (LRP5/6), 3 followed by phosphorylation of LRP5/6, recruitment of Dishevelled to the plasma membrane to interact with Frizzled, and stabilization of cytosolic ␤-catenin (10).…”

Molecular mechanisms of niclosamide antitumor activity

“…Гиперэкспрессия WNT7A стимулировала активность фактора транскрипции TCF/LEF. В следующей работе этих авторов было показано, что под контролем сигнальной системы WNT7A/b-катенин находится экспрессия гена FGF1, кодирующего фактор роста фибробластов [37]. Уровень этого белка является фактором риска при раке яичника и коррелирует с низкой выживаемостью больных [37].…”

“…В следующей работе этих авторов было показано, что под контролем сигнальной системы WNT7A/b-катенин находится экспрессия гена FGF1, кодирующего фактор роста фибробластов [37]. Уровень этого белка является фактором риска при раке яичника и коррелирует с низкой выживаемостью больных [37]. Никлозамид эффективно блокировал сигнальный путь WNT7A/b-катенин, ингибировал активность b-катенина как фактора транскрипции, снижал выживаемость и миграцию клеток.…”

“…Действие никлозамида было более эффективным в клетках с гиперэкспрессией WNT7A. При пероральном введении никлозамида мышам этот препарат ингибировал рост опухоли, растущей внутрибрюшинно (репрезентативная модель рака яичника) [37].…”