Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

A Destabilizer of Both Wnt/β-Catenin and Ras/ERK Pathways Suppresses Cancer Stem Cell Activation in Colorectal Cancer

Version 1 : Received: 4 March 2022 / Approved: 10 March 2022 / Online: 10 March 2022 (14:26:20 CET)

A peer-reviewed article of this Preprint also exists.

Choi, J.K.; Kwak, I.-S.; Yoon, S.-B.; Cho, H.; Moon, B.-S. A Small Molecule Promoting Neural Differentiation Suppresses Cancer Stem Cells in Colorectal Cancer. Biomedicines 2022, 10, 859. Choi, J.K.; Kwak, I.-S.; Yoon, S.-B.; Cho, H.; Moon, B.-S. A Small Molecule Promoting Neural Differentiation Suppresses Cancer Stem Cells in Colorectal Cancer. Biomedicines 2022, 10, 859.

Journal reference: Biomedicines 2022, 10, 859
DOI: 10.3390/biomedicines10040859

Abstract

Cancer stem cells (CSCs) are a tumor cell subpopulation that drives tumor progression and metastasis, leading to poor overall survival of patients. In colorectal cancer (CRC), hyper-activation of Wnt/β-catenin signaling by mutation of both Adenomatous polyposis coli (APC) and K-Ras increases the size of the CSC population. We previously showed that the CPD0857 inactivates Wnt/β-catenin signaling by promoting ubiquitin-dependent proteasomal degradation of β-catenin and Ras proteins, thereby decreasing proliferation and increasing apoptosis of CRC lines. CPD0857 also decreased growth and invasiveness of CRC cells harboring mutant K-Ras resistant to EGFR mAb therapy. Here, we show that CPD0857 treatment decreases proliferation and increases neuronal differentiation of neural progenitor cells (NPCs). CDP0857 effectively reduced expression of CSC markers and suppressed self-renewal capacity. CPD0857 treatment also inhibited proliferation and expression of CSC markers in D-K-Ras MT cells carrying K-Ras, APC and PI3K mutations, indicating inhibition of PI3K/AKT signaling. Moreover, CPD0857-treated xenograft mice showed regression of tumor growth and decreased numbers of CSCs in tumors. We conclude that CPD0857 could serve as the basis of a drug development strategy targeting CSCs activated through Wnt/β-catenin-Ras MAPK-PI3K/AKT signaling in CRCs.

Keywords

Colorectal cancer; Cancer stem cell; Neural progenitor cell; Wnt/β-catenin; K-Ras

Subject

MEDICINE & PHARMACOLOGY, Gastroenterology

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