Paris Saponin II inhibits colorectal carcinogenesis by regulating mitochondrial fission and NF-κB pathway.
Paris Saponin II inhibits colorectal carcinogenesis by regulating mitochondrial fission and NF-κB pathway.
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重楼皂素 II 通过调节线粒体裂变和 NF-κB 通路抑制结直肠癌发生
DOI：
10.1016/j.phrs.2018.11.029
复制
发表时间：
2019-01
影响因子：
9.3
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Chen M;Ye K;Zhang B;Xin Q;Li P;Kong AN;Wen X;Yang J
结直肠癌(CRC)是世界范围内癌症相关发病率和死亡率的主要原因之一。越来越多的证据表明，线粒体动力学与包括结直肠癌在内的肿瘤发生密切相关。重楼皂苷II(PSII)是从重楼中提取的一种主要的甾体皂苷，已成为一种潜在的抗癌药物。然而，PSII对结直肠癌的影响及其潜在机制仍不清楚。在本研究中，我们发现PSII诱导了HT29和HCT116细胞的凋亡并抑制了集落形成，并使细胞周期停滞在G1期。PSII通过使Ser616处的Drp1去磷酸化，抑制ERK1/2的磷酸化和线粒体Dynamin-Related Protein 1(Drp1)的易位，从而抑制线粒体分裂。PSⅡ还通过抑制IKKκ和p65的易位而抑制了NF-βB的激活。基因敲除后，HCT116细胞中p65及其靶基因Cyclin D1和c-Myc的核表达显著下调，证实了线粒体的分裂与NF-κB途径有关。沉默DRP1可增强PSII对p65磷酸化及细胞周期蛋白D1和c-Myc表达的抑制作用，提示PSII对细胞周期蛋白D1和c-Myc的抑制作用可能与其抑制DRP1和NF-κB的激活有关。体内研究表明，PSII显著减小了移植瘤的大小，并抑制了Ser616处ERK1/2和Drp1的磷酸化。综上所述，我们的结果提示PSII可以抑制结直肠癌的发生，至少部分是通过调节线粒体分裂和NF-κB途径实现的。
Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide. Accumulating evidence suggests that mitochondrial dynamics are closely implicated in carcinogenesis including CRC. Paris Saponin II (PSII), a major steroidal saponin extracted from Rhizoma Paris polyphylla, has emerged as a potential anticancer agent. However, the effects of PSII on CRC and its underlying mechanisms remain unknown. In the present study, we found PSII induced apoptosis and inhibited colony formation in HT 29 and HCT 116 cells, and cell cycle arrest in G1 phase. PSII inhibited the phosphorylation of ERK1/2 and mitochondrial translocation of dynamin-related protein 1 (Drp1) by dephosphorylating Drp1 at Ser616, leading to the suppression of mitochondrial fission. PSII also suppressed NF-κB activation as a result of the inhibition of IKKβ and p65 translocation. Drp1 knockdown remarkably downregulated the nuclear expression of p65 and its target genes cyclin D1 and c-Myc in HCT 116 cell, confirming the link between mitochondrial fission and NF-κB pathway. Silencing of Drp 1 enhanced the inhibitory effects of PSII on p65 phosphorylation and the expressions of cyclin D1 and c-Myc, revealing that the inhibitory effects of PSII on cyclin D1 and c-Myc were relevant in the suppression of Drp1 and NF-κB activation. An in vivo study demonstrated PSII remarkably decreased the xenograft tumor size and suppressed the phosphorylation of ERK1/2 and Drp1 at Ser616. Taken together, our results suggested that PSII could inhibit colorectal carcinogenesis, at least in part, by regulating mitochondrial fission and NF-κB pathway.
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DOI：
10.3390/medsci6020031
发表时间：
2018-04-13
期刊：
Medical sciences (Basel, Switzerland)
影响因子：
--
作者：
Testa U;Pelosi E;Castelli G
通讯作者：
Castelli G
影响因子：
1.2
作者：
Bialkowska, Agnieszka B.;Ghaleb, Amr M.;Yang, Vincent W.
通讯作者：
Yang, Vincent W.
影响因子：
16
作者：
Serasinghe, Madhavika N.;Wieder, Shira Y.;Renault, Thibaud T.;Elkholi, Rana;Asciolla, James J.;Yao, Jonathon L.;Jabado, Omar;Hoehn, Kyle;Kageyama, Yusuke;Sesaki, Hiromi;Chipuk, Jerry E.
通讯作者：
Chipuk, Jerry E.
DOI：
10.1007/s00018-016-2451-3
发表时间：
2017-06
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Trotta AP;Chipuk JE
通讯作者：
Chipuk JE
影响因子：
254.7
作者：
Parkin, DM;Bray, F;Pisani, P
通讯作者：
Pisani, P