Abstract: Verticillin A is a diketopiperazine compound which was previously isolated from Amanita flavorubescens Alk (containing parasitic fungi Hypomyces hyalines (Schw.) Tul.). Here, we initially found, by wound healing assay and Transwell assay in vitro, that verticillin A possesses an inhibitory effect against the migration and invasion of the human colon cancer cell. Subsequently, c-mesenchymal-epithelial transition factor (c-Met) was identified as a molecular target of verticillin A by screening key genes related to cell migration. Verticillin A-mediated c-Met suppression is at the transcriptional level. Further study demonstrated that verticillin A suppressed c-MET phosphorylation and decreased c-MET protein level. In addition, verticillin A inhibited the phosphorylation of c-MET downstream molecules including rat sarcoma (Ras)-associated factor (Raf), extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Overexpression of Erk partially reversed the verticillin A-mediated anti-metastasis action in the human colon cancer cell. More importantly, verticillin A also inhibited cancer cell metastasis in vivo. Thus, verticillin A can significantly inhibit the migration and invasion of colon cancer cells by targeting c-Met and inhibiting Ras/Raf/mitogen-activated extracellular signal-regulated kinase (MEK)/ERK signaling pathways. Therefore, we determined that verticillin A is a natural compound that can be further developed as an anti-metastatic drug in human cancers.

轮枝孢菌素A靶向c-Met抑制结肠癌细胞的迁移和侵袭

[1]Arnold L, Enders J, Thomas SM, 2017. Activated HGF-c-Met axis in head and neck cancer. Cancers, 9(12):169.

[2]Birchmeier C, Birchmeier W, Gherardi E, et al., 2003. Met, metastasis, motility and more. Nat Rev Mol Cell Biol, 4(12):915-925.

[3]Budchart P, Khamwut A, Sinthuvanich C, et al., 2017. Partially purified Gloriosa superba peptides inhibit colon cancer cell viability by inducing apoptosis through p53 upregulation. Am J Med Sci, 354(4):423-429.

[4]Chaffer CL, Weinberg RA, 2011. A perspective on cancer cell metastasis. Science, 331(6024):1559-1564.

[5]Chiche A, Di-Cicco A, Sesma-Sanz L, et al., 2019. p53 controls the plasticity of mammary luminal progenitor cells downstream of Met signaling. Breast Cancer Res, 21:13.

[6]Christiano AP, Yoshida BA, Dubauskas Z, et al., 2000. Development of markers of prostate cancer metastasis: review and perspective. Urol Oncol, 5(5):217-223.

[7]Cohen SA, Yu M, Baker K, et al., 2017. The CpG island methylator phenotype is concordant between primary colorectal carcinoma and matched distant metastases. Clin Epigenetics, 9:46.

[8]D'Amico L, Belisario D, Migliardi G, et al., 2016. c-MET inhibition blocks bone metastasis development induced by renal cancer stem cells. Oncotarget, 7(29):45525-45537.

[9]https://doi.org/10.18632/oncotarget.9997

[10]Du PC, Liang HB, Fu XW, et al., 2019. SLC25A22 promotes proliferation and metastasis by activating MAPK/ERK pathway in gallbladder cancer. Cancer Cell Int, 19:33.

[11]Engstrom PF, 2012. Ten years of progress in colon cancer therapy. J Natl Compr Canc Netw, 10(5):574-576.

[12]Fan JX, Zheng DW, Rong L, et al., 2017. Targeting epithelial-mesenchymal transition: metal organic network nano-complexes for preventing tumor metastasis. Biomaterials, 139:116-126.

[13]Fodde R, Smits R, Clevers H, 2001. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer, 1:55-67.

[14]Gardner FP, Serie DJ, Salomao DR, et al., 2014. c-MET expression in primary and liver metastases in uveal melanoma. Melanoma Res, 24(6):617-620.

[15]Gholamin S, Fiuji H, Maftouh M, et al., 2014. Targeting c-MET/HGF signaling pathway in upper gastrointestinal cancers: rationale and progress. Curr Drug Targets, 15(14):1302-1311.

[16]Giordano S, di Renzo MF, Olivero M, et al., 1992. The c-met/ HGF receptor in human tumours. Eur J Cancer Prev, 1(6):45-50.

[17]Glodde N, Bald T, van den Boorn-Konijnenberg D, et al., 2017. Reactive neutrophil responses dependent on the receptor tyrosine kinase c-MET limit cancer immunotherapy. Immunity, 47(4):789-802.e9.

[18]Huang KH, Sung IC, Fang WL, et al., 2018. Correlation between HGF/c-Met and Notch1 signaling pathways in human gastric cancer cells. Oncol Rep, 40(1):294-302.

[19]Hui AY, Meens JA, Schick C, et al., 2009. Src and FAK mediate cell-matrix adhesion-dependent activation of Met during transformation of breast epithelial cells. J Cell Biochem, 107(6):1168-1181.

[20]Jia YT, Dai GY, Wang JX, et al., 2016. c-MET inhibition enhances the response of the colorectal cancer cells to irradiation in vitro and in vivo. Oncol Lett, 11(4):2879-2885.

[21]Kim HS, Chon HJ, Kim H, et al., 2018. MET in gastric cancer with liver metastasis: the relationship between MET amplification and Met overexpression in primary stomach tumors and liver metastasis. J Surg Oncol, 117(8):1679-1686.

[22]Kiselev VY, Juvin V, Malek M, et al., 2015. Perturbations of PIP3 signalling trigger a global remodelling of mRNA landscape and reveal a transcriptional feedback loop. Nucleic Acids Res, 43(20):9663-9679.

[23]Kou LF, Yao Q, Sivaprakasam S, et al., 2017. Dual targeting of L-carnitine-conjugated nanoparticles to OCTN2 and ATB^0,+ to deliver chemotherapeutic agents for colon cancer therapy. Drug Deliv, 24(1):1338-1349.

[24]Kurtzeborn K, Kwon HN, Kuure S, 2019. MAPK/ERK signaling in regulation of renal differentiation. Int J Mol Sci, 20(7):1779.

[25]Lee SJ, Lee J, Park SH, et al., 2018. c-MET overexpression in colorectal cancer: a poor prognostic factor for survival. Clin Colorectal Cancer, 17(3):165-169.

[26]Lino-Silva LS, Guzmán-López JC, Zepeda-Najar C, et al., 2019. Overall survival of patients with colon cancer and a prolonged time to surgery. J Surg Oncol, 119(4):503-509.

[27]Liu FY, Liu QQ, Yang DF, et al., 2011. Verticillin A overcomes apoptosis resistance in human colon carcinoma through DNA methylation-dependent upregulation of BNIP3. Cancer Res, 71(21):6807-6816.

[28]Lu CW, Yang DF, Sabbatini ME, et al., 2018. Contrasting roles of H3K4me3 and H3K9me3 in regulation of apoptosis and gemcitabine resistance in human pancreatic cancer cells. BMC Cancer, 18:149.

[29]Mao D, Feng L, Gong H, 2018. The antitumor and immunomodulatory effect of Yanghe decoction in breast cancer is related to the modulation of the JAK/STAT signaling pathway. Evid Based Complement Alternat Med, 2018: 8460526.

[30]Mihailidou C, Karamouzis MV, Schizas D, et al., 2017. Co-targeting c-Met and DNA double-strand breaks (DSBs):therapeutic strategies in BRCA-mutated gastric carcinomas. Biochimie, 142:135-143.

[31]Mo HN, Liu P, 2017. Targeting MET in cancer therapy. Chronic Dis Transl Med, 3(3):148-153.

[32]Oh BY, Park YA, Huh JW, et al., 2018. Prognostic impact of tumor-budding grade in stages 1–3 colon cancer: a retrospective cohort study. Ann Surg Oncol, 25(1):204-211.

[33]Organ SL, Tsao MS, 2011. An overview of the c-MET signaling pathway. Ther Adv Med Oncol, 3(1_Suppl):S7-S19.

[34]Pan Y, Cheung ST, Tong JHM, et al., 2018. Granulin epithelin precursor promotes colorectal carcinogenesis by activating MARK/ERK pathway. J Transl Med, 16:150.

[35]Parizadeh SM, Jafarzadeh-Esfehani R, Fazilat-Panah D, et al., 2019. The potential therapeutic and prognostic impacts of the c-MET/HGF signaling pathway in colorectal cancer. IUBMB Life, 71(7):802-811.

[36]Paschall AV, Yang DF, Lu CW, et al., 2015. H3K9 trimethylation silences Fas expression to confer colon carcinoma immune escape and 5-fluorouracil chemoresistance. J Immunol, 195(4):1868-1882.

[37]Pereira SS, Monteiro MP, Costa MM, et al., 2019. MAPK/ERK pathway inhibition is a promising treatment target for adrenocortical tumors. J Cell Biochem, 120(1):894-906.

[38]Printz C, 2017. Some stage III colon cancer patients may need only half of the standard chemotherapy course. Cancer, 123(20):3871.

[39]Ren Y, Cao B, Law S, et al., 2005. Hepatocyte growth factor promotes cancer cell migration and angiogenic factors expression: a prognostic marker of human esophageal squamous cell carcinomas. Clin Cancer Res, 11(17):6190-6197.

[40]Saigusa S, Toiyama Y, Tanaka K, et al., 2012. Inhibition of HGF/cMET expression prevents distant recurrence of rectal cancer after preoperative chemoradiotherapy. Int J Oncol, 40(2):583-591.

[41]Sipos F, Galamb O, 2012. Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions in the colon. World J Gastroenterol, 18(7):601-608.

[42]Thayaparan T, Spicer JF, Maher J, 2016. The role of the HGF/Met axis in mesothelioma. Biochem Soc Trans, 44(2):363-370.

[43]Wei DY, Geng F, Liang SM, et al., 2017. CAF-derived HGF promotes cell proliferation and drug resistance by up- regulating the c-Met/PI3K/Akt and GRP78 signalling in ovarian cancer cells. Biosci Rep, 37(2):BSR20160470.

[44]Xiang C, Chen JX, Fu PF, 2017. HGF/Met signaling in cancer invasion: the impact on cytoskeleton remodeling. Cancers, 9(5):44.

[45]Zewdu A, Lopez G, Braggio D, et al., 2016. Verticillin A inhibits leiomyosarcoma and malignant peripheral nerve sheath tumor growth via induction of apoptosis. Clin Exp Pharmacol, 6(6):221.

[46]Zhang QW, Ye ZD, Shi L, 2019. c-Met kinase inhibitors: an update patent review (2014–2017). Expert Opin Ther Pat, 29(1):25-41.