Cucurbitacin E Chemosensitizes Colorectal Cancer Cells via Mitigating TFAP4/Wnt/β-Catenin Signaling

Chemoresistance and toxicity are
the main obstacles that limit
the efficacy of 5-fluorouracil (5-FU) in colorectal cancer (CRC) therapy.
Hence, it is urgent to identify new adjuvants that can sensitize CRC
cells to conventional chemotherapeutic approaches. Cucurbitacin E
(CE) is a natural triterpenoid, widely distributed in dietary plants,
and shows antitumor effects. Here, we report that CE enhances the
sensitivity of CRC cells to chemotherapy via attenuating the expression
of adenosine 5′-triphosphate (ATP)-binding cassette transporters
ABCC1 and MDR1. Combined with CE-functionalized magnetite nanoparticles
and gene ontology analysis, we found that CE-binding proteins may
involve Wnt/β-catenin signaling. To validate the findings, β-catenin
was upregulated in drug-resistant cell lines, and the synergistic
effects of CE and chemotherapeutics were accompanied by the downregulation
of β-catenin. Moreover, TFAP4 was identified as an intracellular
target of CE. Remarkably, the combination of CE and 5-FU treatment
attenuated β-catenin, MDR1, and ABCC1 expressions, while TFAP4
overexpression reversed their expressions by 2.68 ± 0.46-, 0.72
± 0.44-, and 0.93 ± 0.21-fold, respectively. Thus, our results
indicate that CE sensitizes CRC cells to chemotherapy by decreasing
the TFAP4/Wnt/β-catenin signaling, suggesting that the dietary
compound CE can be used as a chemosensitizing adjuvant for CRC treatment.