Targeting DCLK1 overcomes 5‐fluorouracil resistance in colorectal cancer through inhibiting CCAR1/β‐catenin pathway‐mediated cancer stemness

Abstract

Background To date, 5‐fluorouracil‐based chemotherapy is very important for locally advanced or metastatic colorectal cancer (CRC). However, chemotherapy resistance results in tumor recurrence and metastasis, which is a major obstacle for treatment of CRC. Methods In the current research, we establish 5‐fluorouracil resistant cell lines and explore the potential targets associated with 5‐fluorouracil resistance in CRC. Moreover, we perform clinical specimen research, in vitro and in vivo experiments and molecular mechanism research, to reveal the biological effects and the mechanism of DCLK1 promoting 5‐fluorouracil resistance, and to clarify the potential clinical value of DCLK1 as a target of 5‐fluorouracil resistance in CRC. Results We discover that doublecortin‐like kinase 1 (DCLK1), a cancer stem cell maker, is correlated with 5‐fluorouracil resistance, and functionally promotes cancer stemness and 5‐fluorouracil resistance in CRC. Mechanistically, we elucidate that DCLK1 interacts with cell cycle and apoptosis regulator 1 (CCAR1) through the C‐terminal domain, and phosphorylates CCAR1 at the Ser343 site, which is essential for CCAR1 stabilisation. Moreover, we find that DCLK1 positively regulates β‐catenin signalling via CCAR1, which is responsible for maintaining cancer stemness. Subsequently, we prove that blocking β‐catenin inhibits DCLK1‐mediated 5‐fluorouracil resistance in CRC cells. Importantly, we demonstrate that DCLK1 inhibitor could block CCAR1/β‐catenin pathway‐mediated cancer stemness and consequently suppresses 5‐fluorouracil resistant CRC cells in vitro and in vivo. Conclusions Collectively, our findings reveal that DCLK1 promotes 5‐fluorouracil resistance in CRC by CCAR1/β‐catenin pathway‐mediated cancer stemness, and suggest that targeting DCLK1 might be a promising method to eliminate cancer stem cells for overcoming 5‐fluorouracil resistance in CRC.

PRAME Is a Novel Target of Tumor-Intrinsic Gas6/Axl Activation and Promotes Cancer Cell Invasion in Hepatocellular Carcinoma

“…In HCC, the interaction of CCAR1 with β-catenin induces cancer stem cell enrichment via activation of Wnt target genes [61]. The same mechanism is utilized in 5-fluorouracil resistant colorectal cancer models as CCAR1 associates with β-catenin and triggers a stemness-like phenotype by inducing Myc among others [62]. Knockdown of SH3PXD2B reduces invadopodia formation and subsequently lung metastasis in in vivo models [63].…”

UVRAG Promotes Tumor Progression through Regulating SP1 in Colorectal Cancer

“…UVRAG expression in HCT116 cells was predominantly lower than that in HCT116-self cells (Figure 3E). Doublecortin-like kinase 1 (DCLK) was reported as a marker of CSCs, involved in resistance to 5-Fu and radiotherapy [15,16]. Therefore, UVRAG expression in DCLK+ HCT116 and DCLK-HCT116 cells was detected, and it was found that DCLK+ HCT116 cells showed a higher UVRAG expression (Figure 3F), suggesting that UVRAG might be associated with CRC stem cells.…”

Deciphering treatment resistance in metastatic colorectal cancer: roles of drug transports, EGFR mutations, and HGF/c-MET signaling

“…Wnt/β-catenin induced CRC treatment resistance has been attributed to mainly three aspects: highly metastatic CSCs, regulation of non-coding RNA, and TME regulation ( Zhao et al, 2022 ). For instance, doublecortin-like kinase 1 (DCLK1), a cancer stem cell marker could confer the 5-FU resistance in CRC via the aberrant activation of Wnt/β-catenin signaling ( Wang et al, 2022a ). Cetuximab resistance was found to be related to the upregulation of miR-199b-3p via the activation of the Wnt/β-catenin pathway ( Han et al, 2022 ).…”