Hilliard Tyvette S, Miklossy Gabriella, Chock Christopher, Yue Peibin, Williams Philip, Turkson James
Cancer Biology and Natural Products Program, University of Hawai'i Cancer Center, Honolulu, Hawaii.
Department of Chemistry, University of Hawai'i at Manoa, Honolulu, Hawaii.
Mol Cancer Ther. 2017 Apr;16(4):601-613. doi: 10.1158/1535-7163.MCT-16-0291. Epub 2017 Jan 9.
Studies with 15α-methoxypuupehenol (15α-MP), obtained from the extracts of species, identified putative targets that are associated with its antitumor effects against human glioblastoma and breast cancer. In the human glioblastoma (U251MG) or breast cancer (MDA-MB-231) cells, treatment with 15α-MP repressed pY705Stat3, pErk1/2, pS147CyclinB1, pY507Alk (anaplastic lymphoma kinase), and pY478ezrin levels and induced pS10merlin, without inhibiting pJAK2 (Janus kinase) or pAkt induction. 15α-MP treatment induced loss of viability of breast cancer (MDA-MB-231, MDA-MB-468) and glioblastoma (U251MG) lines and glioblastoma patient-derived xenograft cells (G22) that harbor aberrantly active Stat3, with only moderate or little effect on the human breast cancer, MCF7, colorectal adenocarcinoma Caco-2, normal human lung fibroblast, WI-38, or normal mouse embryonic fibroblast (MEF Stat3) lines that do not harbor constitutively active Stat3 or the Stat3-null (Stat3) mouse astrocytes. 15α-MP-treated U251MG cells have severely impaired F-actin organization and altered morphology, including the cells rounding up, and undergo apoptosis, compared with a moderate, reversible morphology change observed for similarly treated mouse astrocytes. Treatment further inhibited U251MG or MDA-MB-231 cell proliferation, anchorage-independent growth, colony formation, and migration while only moderately or weakly affecting MCF7 cells or normal mouse astrocytes. Oral gavage delivery of 15α-MP inhibited the growth of U251MG subcutaneous tumor xenografts in mice, associated with apoptosis in the treated tumor tissues. Results together suggest that the modulation of Stat3, CyclinB1, Alk, ezrin, merlin, and Erk1/2 functions contributes to the antitumor effects of 15α-MP against glioblastoma and breast cancer progression. .
对从该物种提取物中获得的15α-甲氧基普佩酚（15α-MP）进行的研究，确定了与其对人胶质母细胞瘤和乳腺癌的抗肿瘤作用相关的假定靶点。在人胶质母细胞瘤（U251MG）或乳腺癌（MDA-MB-231）细胞中，用15α-MP处理可抑制pY705Stat3、pErk1/2、pS147CyclinB1、pY507Alk（间变性淋巴瘤激酶）和pY478埃兹蛋白水平，并诱导pS10merlin，而不抑制pJAK2（Janus激酶）或pAkt的诱导。15α-MP处理导致乳腺癌（MDA-MB-231、MDA-MB-468）和胶质母细胞瘤（U251MG）细胞系以及胶质母细胞瘤患者来源的异种移植细胞（G22）的活力丧失，这些细胞中Stat3异常激活，而对人乳腺癌MCF7、结肠腺癌Caco-2、正常人肺成纤维细胞WI-38或正常小鼠胚胎成纤维细胞（MEF Stat3）细胞系的影响较小或几乎没有影响，这些细胞系不具有组成性激活的Stat3或Stat3基因敲除（Stat3）小鼠星形胶质细胞。与同样处理的小鼠星形胶质细胞观察到的中度、可逆的形态变化相比，15α-MP处理的U251MG细胞的F-肌动蛋白组织严重受损，形态改变，包括细胞变圆，并发生凋亡。该处理进一步抑制了U251MG或MDA-MB-231细胞的增殖、非锚定依赖性生长、集落形成和迁移，而对MCF7细胞或正常小鼠星形胶质细胞的影响仅为中度或轻度。经口灌胃给予15α-MP可抑制小鼠U251MG皮下肿瘤异种移植瘤的生长，这与处理后的肿瘤组织中的凋亡有关。结果共同表明，对Stat3、CyclinB1、Alk、埃兹蛋白、merlin和Erk1/2功能的调节有助于15α-MP对胶质母细胞瘤和乳腺癌进展的抗肿瘤作用。
