Heteronemin and Tetrac Induce Anti-Proliferation by Blocking EGFR-Mediated Signaling in Colorectal Cancer Cells

被引：7

作者：

Unson, Sukanya ^{[1
,2
]}

Chang, Tung-Cheng ^{[3
,4
]}

Yang, Yung-Ning ^{[5
,6
]}

Wang, Shwu-Huey ^{[7
,8
]}

Huang, Chi-Hung ^{[9
]}

Crawford, Dana R. ^{[10
]}

Huang, Haw-Ming ^{[11
]}

Li, Zi-Lin ^{[12
,13
]}

Lin, Hung-Yun ^{[13
,14
,15
,16
,17
]}

Whang-Peng, Jacqueline ^{[16
]}

Wang, Kuan

Davis, Paul J. ^{[17
,18
]}

Li, Wen-Shan ^{[19
,20
]}

机构：

[1] Taipei Med Univ, Grad Inst Canc Mol Biol & Drug Discovery, Coll Med Sci & Technol, Taipei 11031, Taiwan

[2] Acad Sinica, Taipei 11031, Taiwan

[3] Taipei Med Univ, Div Colorectal Surg, Dept Surg, Shuang Ho Hosp, Taipei 11031, Taiwan

[4] Taipei Med Univ, Sch Med, Div Colorectal Surg, Dept Surg, Taipei 11031, Taiwan

[5] I Shou Univ, Sch Med, Kaohsiung 82445, Taiwan

[6] E DA Hosp, Dept Pediat, Kaohsiung 82445, Taiwan

[7] Taipei Med Univ, Res Dev Dept, Core Facil Ctr, Taipei 11031, Taiwan

[8] Taipei Med Univ, Dept Biochem & Mol Cell Biol, Coll Med, Taipei 11031, Taiwan

[9] Cathay Gen Hosp, Div Cardiol, Dept Internal Med, Taipei 10630, Taiwan

[10] Albany Med Coll, Dept Immunol & Microbial Dis, Albany, NY 12208 USA

[11] Taipei Med Univ, Sch Dent, Coll Oral Med, Taipei 11031, Taiwan

[12] Taipei Med Univ, Grad Inst Nanomed & Med Engn, Coll Med Engn, Taipei 11031, Taiwan

[13] Taipei Med Univ, Grad Inst Canc Mol Biol & Drug Discovery, Coll Med Sci & Technol, Taipei 11031, Taiwan

[14] Taipei Med Univ, TMU Res Ctr Canc Translat Med, Taipei 11031, Taiwan

[15] Taipei Med Univ, Tradit Herbal Med Res Ctr, Taipei Med Univ Hosp, Taipei 11031, Taiwan

[16] Taipei Med Univ, Wan Fang Hosp, Ctr Canc, Taipei 11031, Taiwan

[17] Albany Coll Pharm & Hlth Sci, Pharmaceut Res Inst, Albany, NY 12208 USA

[18] Albany Med Coll, Dept Med, Albany, NY 12208 USA

[19] Acad Sinica, Inst Chem, Lab Chem Biol & Med Chem, Taipei 10617, Taiwan

[20] Natl Sun Yat Sen Univ, Doctoral Degree Program Marine Biotechnol, Kaohsiung 80424, Taiwan

来源：

MARINE DRUGS | 2022年 / 20卷 / 08期

关键词：

heteronemin; tetrac; colorectal cancer; KRAS; EGFR signaling; TETRAIODOTHYROACETIC ACID; GENE-EXPRESSION; PD-L1; THERAPY;

D O I：

10.3390/md20080482

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Overexpressed EGFR and mutant K-Ras 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 Hippospongia sp., Heteronemin, has been shown to induce anti-proliferation in several types of cancers. A thyroxine-deaminated analogue, tetrac, binds to integrin alpha v beta 3 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 (KRAS WT CRC) and HCT-116 cells (KRAS 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 (KRAS WT CRC). Results by NanoString technology and RT-qPCR revealed that heteronemin and combined treatment suppressed the expression of EGFR and downstream genes in HCT-116 cells (KRAS MT CRC). Heteronemin or combined treatment downregulated genes associated with cancer progression and decreased cell motility. Heteronemin or the combined treatment suppressed PD-L1 expression in both cancer cell lines. However, only tetrac and the combined treatment inhibited PD-L1 protein accumulation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS 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 KRAS resistance for anti-EGFR therapy.

引用

页数：21

共 43 条

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