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

Abstract

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.

Cucurbitacin E inhibits cellular proliferation and induces apoptosis in melanoma by suppressing HSDL2 expression

“…Previous reports have also shown that CuE has remarkable potential in suppressing the growth of multiple cancer cell types [ 18 , 30 , 31 ]. CuE can inhibit cell proliferation, induce cell cycle arrest and enhance apoptotic cell death by modulating the STAT3, MAPK, PI3K/AKT, Wnt/beta-catenin and mTOR signalling pathways [ 17 , 19 , 32 – 34 ]. CuE can also suppress angiogenesis by inhibiting the VEGFR2-mediated JAK2 − STAT3 signalling pathway and cancer cell metastasis by inhibiting depolymerization of actin filaments [ 35 , 36 ].…”

“…CuE can also suppress angiogenesis by inhibiting the VEGFR2-mediated JAK2 − STAT3 signalling pathway and cancer cell metastasis by inhibiting depolymerization of actin filaments [ 35 , 36 ]. In addition, CuE can enhance the sensitivity of tumours such as gastric cancer and colorectal cancer to conventional chemotherapeutic drugs [ 17 , 18 ]. Fortunately, our data demonstrated that CuE could inhibit HSDL2 expression and melanoma cell proliferation and induce cell apoptosis, a significant target for slowing tumour development, by suppressing the ERK and AKT pathways and reducing xenograft melanoma growth.…”

“…Cucurbitacin E (CuE) is a member of the cucurbitacin family, which is a group of tetracyclic triterpenoids extracted from cucurbitaceous plants [ 16 ]. Accumulated evidence has demonstrated that CuE has effective pharmacological properties, such as lipid reduction, hepatic protection, anti-inflammation, and antitumour activity [ 17 ]. The potential anticarcinogenic properties of CuE on diverse tumour types, such as gastric cancer, lung cancer, breast cancer and ovarian cancer, have been well studied [ 18 – 21 ].…”

Advances in the synergistic and toxic attenuating effect of traditional Chinese medicine in cancer treatment

“…治疗的增敏剂 [21] 。肠道微生物可通过改变药物代谢能力和宿主代谢稳态影响化 疗药的抗肿瘤疗效。有研究发现，灵芝孢子中提取的多糖通过重塑肠道菌群抑制 肿瘤细胞代谢，增强乳腺癌对紫杉醇的敏感性，并可恢复紫杉醇引发的肠道菌群 失调 [22] 。 在我国， 临床医生根据辨证施治原则常采用不同的中药方剂与化疗药相结合， 以达到肿瘤治疗减毒增效的目的。 一项对参芪扶正注射液治疗晚期胃癌的系统荟 萃分析发现，与单独采用化疗方法相比，化疗联合参芪扶正注射液可提高患者的 完全缓解(优势比 OR=1.68)和部分缓解有效率(OR=1.32)，并显著改善患者 生活质量， 减少恶心、 呕吐、 口腔粘膜炎、 白细胞减少等不良反应的发生 (OR=3.05) [23] 。此外，与单独使用铂类化疗药相比，参芪扶正注射液与铂类化疗药联合治 疗晚期非小细胞肺癌(NSCLC)和结直肠癌使肿瘤治疗响应率提高 19%，并能 显著降低多种不良反应发生率 [24,25] 。 从中药薏苡仁中提取的有效成分康莱特注射 液联合化疗药治疗晚期 NSCLC 的临床试验表明，与单独使用化疗药相比，联合 用药可显著提高患者的客观响应率 (RR=1.35) ， 提高患者生存质量 (RR=2.04)， 并降低胃肠道副反应风险(RR=0.53) [26][27][28]…”

Therapeutic strategies targeting Wnt/β‑catenin signaling for colorectal cancer (Review)

“…In addition to the aforementioned natural compounds, certain other extractions from natural products also inhibit CRC growth and induce CRC cell apoptosis via inactivation of the Wnt/β-catenin signaling pathway. Their inhibitory mechanisms in this pathway mainly include: i) Downregulating the levels of β-catenin or inhibiting nuclear translocation of β-catenin, such as TKP extracted from a medicinal plant Trichosanthes kirilowii ( 2 ), magnolol derived from Magnolia obovata ( 135 ), ethanol extract of Scutellaria barbata D. Don (EESB) ( 136 ), jatrorrhizine (a main component of Rhizoma coptidis ) ( 46 ) and pristimerin (a natural triterpenoid) ( 137 ); ii) downregulating phosphosylated-GSK-3β or upregulating GSK-3β, for example TKP ( 138 ); iii) inhibiting the expression of Wnt downstream target genes, including magnolol ( 135 ), EESB ( 136 ), sulforaphane extracted from cruciferous vegetables ( 18 ) and pristimerin ( 137 ); iv) blocking the interaction between β-catenin and TCF4 complexes, such as magnolol ( 135 ) and 11α, 12α-epoxyleukamenin E isolated from Salvia cavaleriei ( 37 ); v) downregulating invasion-associated proteins MMP-2 and MMP-9, such as TKP ( 138 ); vi) inhibiting EMT via increasing E-cadherin and decreasing N-cadherin, such as jatrorrhizine ( 46 ); and vii) exerting a synergistic effect on the inhibition of CRC, for example, the combination of cucurbitacin E and 5-FU inhibits the expression of β-catenin and chemosensitizes CRC cells via negatively regulating the transcription factor AP4/Wnt/β-catenin axis ( 139 ).…”