ADNP Is a Therapeutically Inducible Repressor of WNT Signaling in Colorectal Cancer

Abstract

Constitutively active WNT signaling is a hallmark of colorectal cancers and a driver of malignant tumor progression. Therapeutic targeting of WNT signaling is difficult due to high pathway complexity and its role in tissue homeostasis. Here, we identify the transcription factor ADNP as a pharmacologically inducible repressor of WNT signaling in colon cancer. We used transcriptomic, proteomic, and analyses to identify ADNP expression in colorectal cancer and cell biology approaches to determine its function. We induced ADNP expression in colon cancer xenografts by low-dose ketamine Clinical associations were determined in a cohort of 221 human colorectal cancer cases. ADNP was overexpressed in colon cancer cells with high WNT activity, where it acted as a WNT repressor. Silencing ADNP expression increased migration, invasion, and proliferation of colon cancer cells and accelerated tumor growth in xenografts Treatment with subnarcotic doses of ketamine induced ADNP expression, significantly inhibited tumor growth, and prolonged survival of tumor-bearing animals. In human patients with colon cancer, high ADNP expression was linked to good prognosis. Our findings indicate that ADNP is a tumor suppressor and promising prognostic marker, and that ketamine treatment with ADNP induction is a potential therapeutic approach that may add benefit to current treatment protocols for patients with colorectal cancer. .

A Positive Feed-Forward Loop between LncRNA-CYTOR and Wnt/β-Catenin Signaling Promotes Metastasis of Colon Cancer

“…6,8,37 Different from mutations in other cancer types, mutations in the key regulatory factors of Wnt/b-catenin signaling are frequent events in colon cancer. 38 Constitutive activation of Wnt/b-catenin signaling, which was reflected by the translocation of b-catenin into the nucleus, may cause the reduction of E-cadherin and subsequent induction of EMT. 39 Until now, LncRNAs participating in the Wnt/b-catenin signaling-induced EMT are still seldom reported.…”

ADNP Upregulation Promotes Bladder Cancer Cell Proliferation via the AKT Pathway

“…In previous studies, ADNP was associated with the de novo mutation that leads to autism-like spectrum disorder (18). However, a recent study suggested that negative ADNP expression in the colon activates the WNT signaling pathway, promoting colon cancer cell migration, invasion, and proliferation (15). We found that ADNP expression was significantly correlated with high pathological grade and advanced clinical stage, indicating that ADNP may be an oncogene of BC that can lead to tumor cell proliferation and tumorigenesis.…”

“…According to the previous research, ADNP loss-of-function mutations have been found to be related to carcinogenesis ( 14 ). It was reported that ADNP can suppress cellular migration, invasion, and proliferation via the WNT signaling pathway in colon carcinoma ( 15 ) and triple-negative breast cancer ( 16 ). By contrast, the activation of the ADNP signaling system, mediated by an endogenous pituitary adenylate cyclase-activating polypeptide, can increase the resistance of malignant peripheral nerve sheath tumor to H 2 O 2 -induced death with serum starvation ( 17 ).…”

Repurposing Established Compounds to Target Pancreatic Cancer Stem Cells (CSCs)

“…Recently, Blaj et al showed that low-dose ketamine induced activity-dependent neuroprotector homeobox (ADNP) expression in a colorectal cancer model. ADNP in turn acted as a Wnt repressor which ultimately led to tumor growth inhibition and prolonged survival of tumor bearing animals [ 60 ].…”