Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.
Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Shuang Ho Hospital, Taipei 11031, Taiwan.
Mar Drugs. 2022 Jul 27;20(8):482. doi: 10.3390/md20080482.
Overexpressed EGFR and mutant play vital roles in therapeutic resistance in colorectal cancer patients. To search for an effective therapeutic protocol is an urgent task. A secondary metabolite in the sponge sp., Heteronemin, has been shown to induce anti-proliferation in several types of cancers. A thyroxine-deaminated analogue, tetrac, binds to integrin αvβ3 to induce anti-proliferation in different cancers. Heteronemin- and in combination with tetrac-induced antiproliferative effects were evaluated. Tetrac enhanced heteronemin-induced anti-proliferation in HT-29 cells ( WT CRC) and HCT-116 cells ( MT CRC). Heteronemin and tetrac arrested cell cycle in different phases. Combined treatment increased the cell accumulation in sub-G1 and S phases. The combined treatment also induced the inactivation of EGFR signaling and downregulated the phosphorylated ERK1/2 protein in both cell lines. Heteronemin and the combination showed the downregulation of the phosphorylated and total PI3K protein in HT-29 cells ( WT CRC). Results by NanoString technology and RT-qPCR revealed that heteronemin and combined treatment suppressed the expression of and downstream genes in HCT-116 cells ( MT CRC). Heteronemin or combined treatment downregulated genes associated with cancer progression and decreased cell motility. Heteronemin or the combined treatment suppressed expression in both cancer cell lines. However, only tetrac and the combined treatment inhibited PD-L1 protein accumulation in HT-29 cells ( WT CRC) and HCT-116 cells ( MT CRC), respectively. In summary, heteronemin induced anti-proliferation in colorectal cancer cells by blocking the EGFR-dependent signal transduction pathway. The combined treatment further enhanced the anti-proliferative effect via PD-L1 suppression. It can be an alternative strategy to suppress mutant resistance for anti-EGFR therapy.
过表达的 EGFR 和突变体在结直肠癌患者的治疗耐药中起着至关重要的作用。寻找有效的治疗方案是当务之急。海绵 sp. 的一种次生代谢物 Heteronemin 已被证明可诱导几种类型的癌症的抗增殖作用。一种甲状腺素脱氨酶类似物 Tetrac 与整合素 αvβ3 结合，可诱导不同癌症的抗增殖作用。评估了 Heteronemin 和与 Tetrac 联合诱导的抗增殖作用。Tetrac 增强了 HT-29 细胞（WTCRC）和 HCT-116 细胞（MTRC）中 Heteronemin 诱导的抗增殖作用。Heteronemin 和 Tetrac 使细胞周期停滞在不同阶段。联合治疗增加了细胞在 sub-G1 和 S 期的积累。联合治疗还诱导了两种细胞系中 EGFR 信号的失活和磷酸化 ERK1/2 蛋白的下调。Heteronemin 和联合治疗在 HT-29 细胞（WTCRC）中显示出磷酸化和总 PI3K 蛋白的下调。NanoString 技术和 RT-qPCR 的结果显示，Heteronemin 和联合治疗抑制了 HCT-116 细胞（MTRC）中 及其下游基因的表达。Heteronemin 或联合治疗下调了与癌症进展相关的基因，并降低了细胞迁移能力。Heteronemin 或联合治疗下调了两种癌细胞系中的 基因表达。然而，只有 Tetrac 和联合治疗抑制了 HT-29 细胞（WTCRC）和 HCT-116 细胞（MTRC）中 PD-L1 蛋白的积累。总之，Heteronemin 通过阻断 EGFR 依赖性信号转导通路诱导结直肠癌细胞的抗增殖作用。联合治疗通过抑制 PD-L1 进一步增强了抗增殖作用。对于抗 EGFR 治疗，它可能是抑制突变体耐药的替代策略。
