Betulinic acid inhibits stemness and EMT of pancreatic cancer cells via activation of AMPK signaling.
Betulinic acid inhibits stemness and EMT of pancreatic cancer cells via activation of AMPK signaling.
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桦木酸通过激活 AMPK 信号传导抑制胰腺癌细胞的干细胞性和 EMT。
DOI：
10.3892/ijo.2018.4604
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发表时间：
2019-01
影响因子：
5.2
通讯作者：
Xu Q
中科院分区：
文献类型：
--
作者：
Sun L;Cao J;Chen K;Cheng L;Zhou C;Yan B;Qian W;Li J;Duan W;Ma J;Qi D;Wu E;Wang Z;Liu Q;Ma Q;Xu Q
癌症干细胞（CSCs）存在于包括胰腺癌在内的各种人类癌症中，具有升高的转移潜能，导致肿瘤复发并引起放化疗抗性。通过调节5′-腺苷一磷酸激活蛋白激酶（AMPK）信号传导而改变细胞生物能量学可能是干性的先决条件。桦木酸（Betulinic acid，BA）是一种具有抗逆转录病毒和抗炎潜力的生物活性化合物，已报道其对包括胰腺癌在内的各种类型的癌症发挥抗癌作用。本研究旨在探讨BA是否通过调节AMPK信号通路抑制胰腺CSC。MTT法和集落形成实验检测胰腺癌细胞的增殖情况。采用创伤划痕法和Transwell侵袭法检测胰腺癌细胞的迁移和侵袭能力。此外，通过逆转录-定量聚合酶链反应和蛋白质印迹法测定候选基因的表达水平。结果显示，BA抑制胰腺癌细胞的增殖和肿瘤球形成，抑制上皮间质转化（EMT）、迁移和侵袭，并降低SRY-box 2（Sox 2）、八聚体结合蛋白4（Oct 4）和Nanog的表达。此外，免疫组化分析证实胰腺癌中磷酸化（P）-AMPK和Sox 2的表达水平之间存在显著的负相关性，表明BA可能激活AMPK信号。值得注意的是，AMPK的敲低逆转了BA对胰腺癌细胞EMT和干细胞的抑制作用。此外，BA逆转吉西他滨对干性的影响，并增强胰腺癌细胞对吉西他滨的敏感性。总的来说，这些结果表明，BA可以通过激活AMPK信号传导有效地抑制胰腺癌细胞的多能性因子表达（Sox 2、Oct 4和Nanog）、EMT和干细胞样表型。因此，BA可能被认为是一种有吸引力的治疗候选物，并且是胰腺癌细胞中干细胞样表型的有效抑制剂。BA作为一种抗癌药物的发展需要进一步研究。
Cancer stem cells (CSCs), which are found in various types of human cancer, including pancreatic cancer, possess elevated metastatic potential, lead to tumor recurrence and cause chemoradiotherapy resistance. Alterations in cellular bioenergetics through the regulation of 5′ adenosine monophosphate-activated protein kinase (AMPK) signaling may be a prerequisite to stemness. Betulinic acid (BA) is a well-known bioactive compound with antiretroviral and anti-inflammatory potential, which has been reported to exert anticancer effects on various types of cancer, including pancreatic cancer. The present study aimed to investigate whether BA could inhibit pancreatic CSCs via regulation of AMPK signaling. The proliferation of pancreatic cancer cells was examined by MTT and colony formation assays. The migratory and invasive abilities of pancreatic cancer cells were assessed using wound-scratch and Transwell invasion assays. In addition, the expression levels of candidate genes were measured by reverse transcription-quantitative polymerase chain reaction and western blotting. The results revealed that BA inhibited the proliferation and tumorsphere formation of pancreatic cancer cells, suppressed epithelial-mesenchymal transition (EMT), migration and invasion, and reduced the expression of three pluripotency factors [SRY-box 2 (Sox2), octamer-binding protein 4 (Oct4) and Nanog]. Furthermore, immunohistochemical analysis confirmed that there was a significant inverse association between the expression levels of phosphorylated (P)-AMPK and Sox2 in pancreatic cancer, and it was revealed that BA may activate AMPK signaling. Notably, knockdown of AMPK reversed the suppressive effects of BA on EMT and stemness of pancreatic cancer cells. In addition, BA reversed the effects of gemcitabine on stemness and enhanced the sensitivity of pancreatic cancer cells to gemcitabine. Collectively, these results indicated that BA may effectively inhibit pluripotency factor expression (Sox2, Oct4 and Nanog), EMT and the stem-like phenotype of pancreatic cancer cells via activating AMPK signaling. Therefore, BA may be considered an attractive therapeutic candidate and an effective inhibitor of the stem-like phenotype in pancreatic cancer cells. Further investigation into the development of BA as an anticancer drug is warranted.
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影响因子：
37.3
作者：
Lei J;Ma J;Ma Q;Li X;Liu H;Xu Q;Duan W;Sun Q;Xu J;Wu Z;Wu E
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影响因子：
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通讯作者：
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DOI：
10.1038/nrc3322
发表时间：
2012-10
期刊：
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影响因子：
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作者：
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DOI：
10.1158/1940-6207.capr-11-0299
发表时间：
2012-03
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
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作者：
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通讯作者：
Sarkar FH