FIBP knockdown attenuates growth and enhances chemotherapy in colorectal cancer via regulating GSK3β-related pathways

Abstract

Colorectal cancer stem cells (CSCs), characterized by self-renewal ability and high expression of proliferative genes, contribute to the chemoresistance of colorectal cancer (CRC). We aimed to identify the molecular mechanisms underlying CRC chemoresistance through comprehensive bioinformatics screenings and experimental confirmation of gene functions. We found that high expression of FGF1 intracellular binding protein (FIBP) was correlated with chemoresistance and poor prognosis in CRC patients. Therefore, the chemoresistant CRC cell line HCT116-CSC with high expression of the stem cell markers CD44 and CD133 was established for further phenotypic tests. FIBP knockdown inhibited proliferation, enhanced chemotherapy effects, and attenuated the stemness markers of CRC cells in vivo and in vitro. Through RNA-seq and gene set enrichment analysis, we identified cyclin D1 as a key downstream target in FIBP-regulated cell cycle progression and proliferation. Moreover, FIBP bound to GSK3β, inhibited its phosphorylation at Tyr216, and activated β-catenin/TCF/cyclin D1 signaling in HCT116-CSCs. Additional GSK3β knockdown reversed the FIBP silencing-induced inhibition of proliferation and decreased stemness marker expression in HCT116-CSCs. Furthermore, DNA methylation profiling suggested that FIBP regulated the stemness of CRC cells via methylation activity that was dependent on GSK3β but independent of β-catenin signaling. Our data illuminate the potential of FIBP as a novel therapeutic target for treating chemoresistant CRC through inhibition of GSK3β-related signaling.

Therapeutic Strategies Targeting Cancer Stem Cells and Their Microenvironment

“…CD44, the transmembrane protein that is the receptor for matrix components such as hyaluronic acid selectin, collagen, and osteopontin, has been proven to help treat acute myeloid leukemia (AML) by inhibiting tumor proliferation, and increasing apoptosis (152, 153). CD133, the glycoprotein also known as prominin-1, is another well-known marker on the CSCs surface and it has been reported to be a useful target in cancers with a large CD133 subpopulation (154, 155). In addition, other drugs approved by FDA are also used for targeting CSC markers such as rituximab (anti-CD20) (156), cetuximab (anti-EGFR) (157–159).…”

Involvement and Targeted Intervention of Mortalin-Regulated Proteome Phosphorylated-Modification in Hepatocellular Carcinoma

“…In addition, GSK3 functions as an important downstream regulatory switch for numerous signaling pathways involved in the formation of tumors, including the regulation of the Wnt/β-catenin pathway ( 39 , 40 ). In the pathway, activated AKT could bind to the GSK3β complex and then phosphorylate GSK3β at Ser9 and increase the β-catenin levels ( 41 , 42 ) but inhibit GSK3β phosphorylation at Tyr216, also causing the activation of β-catenin ( 43 ). Here, we found that the phosphorylation of GSK3β at Ser9 was downregulated, whereas the phosphorylation of GSK3β at Tyr216 was upregulated in mortalin knockdown cells, which inhibited the phosphorylation of β-catenin at several main sites, such as Ser37, Thr41, and Tyr654.…”

Involvement and Targeted Intervention of Mortalin-Regulated Proteome Phosphorylated-Modification in Hepatocellular Carcinoma

“…In addition, GSK3 functions as an important downstream regulatory switch for numerous signaling pathways involved in the formation of tumors, including the regulation of Wnt/β-catenin pathway [31,32]. In the pathway, activated AKT could bind to GSK3β complex and then phosphorylate GSK3β at Ser9 and increased the β-catenin levels [33,34], while inhibited GSK3β phosphorylation at Tyr216 also caused the activation of β-catenin [35]. Here, we found the phosphorylation of GSK3β at Ser9 were downregulated while GSK3β at Tyr216 were upregulated in mortalin knockdown cells, which inhibited the phosphorylation of β-catenin at several main sites such as Ser37, Thr41 and Tyr654.…”