当抑制胰腺癌干细胞时， Umbelliprenin 可诱导自噬和细胞凋亡。

Umbelliprenin induces autophagy and apoptosis while inhibits cancer cell stemness in pancreatic cancer cells.

机构信息

Department of Hepatobiliary and Pancreatic Surgery, Sixth People's Hospital Affiliated Shanghai Jiao Tong University, Shanghai, China.

Department of General Surgery, The Second People' Hospital of Kashgar, 1S, Kashgar, Xinjiang, China.

出版信息

Cancer Med. 2023 Jul;12(14):15277-15288. doi: 10.1002/cam4.6170. Epub 2023 Jul 6.

BACKGROUND

Umbelliprenin is a sesquiterpene coumarin isolated from Artemisia absinthium L. and shows antitumor effects in various cancers by inducing apoptosis. However, the antitumor effect of umbelliprenin in human pancreatic cancer has not been clarified.

METHODS

The antitumor effects were determined by MTT and AnnexinV/PI double staining assay in vitro and xenograft mice in vivo. Autophagy was determined via immunofluorescence analysis. Apoptotic or autophagic related proteins were measured by immunoblotting. The pancreatic cancer cell stemness were determined by mammosphere formation and ALDEFLUOR assay.

RESULTS

It revealed that umbelliprenin inhibited pancreatic cancer cell proliferation in vitro and pancreatic cancer tumor growth in vivo. Moreover, umbelliprenin induced pancreatic cancer cell BxPC3 apoptosis and autophagy as evidenced by upregulated apoptosis and autophagy- related protein expression (p < 0.01). Blocking autophagy by 3-MA or Atg7 knockout enhanced umbelliprenin-induced apoptosis (p < 0.05). Umbelliprenin also reduced pancreatic cancer cell stemness by reducing Oct4, Nanog, and Sox2 mRNA levels (p < 0.01). Mechanistically, umbelliprenin greatly inhibited Akt/mTOR and Notch1 signal pathway.

CONCLUSION

Umbelliprenin may be a novel therapeutic approach for pancreatic cancer treatment.

背景

茵陈炔内酯是从苦艾中分离得到的一种倍半萜香豆素，通过诱导细胞凋亡在多种癌症中显示出抗肿瘤作用。然而，茵陈炔内酯在人胰腺癌细胞中的抗肿瘤作用尚未阐明。

方法

通过 MTT 和 AnnexinV/PI 双染色法在体外和异种移植小鼠体内测定抗肿瘤作用。通过免疫荧光分析测定自噬。通过免疫印迹测定凋亡或自噬相关蛋白。通过乳腺球形成和 ALDEFLUOR 测定测定胰腺癌细胞干性。

结果

结果表明，茵陈炔内酯抑制胰腺癌细胞在体外的增殖和体内的肿瘤生长。此外，茵陈炔内酯诱导胰腺癌细胞 BxPC3 凋亡和自噬，表现为凋亡和自噬相关蛋白表达上调（p<0.01）。通过 3-MA 阻断自噬或 Atg7 敲除增强了茵陈炔内酯诱导的凋亡（p<0.05）。茵陈炔内酯还通过降低 Oct4、Nanog 和 Sox2 mRNA 水平降低胰腺癌细胞干性（p<0.01）。机制上，茵陈炔内酯显著抑制 Akt/mTOR 和 Notch1 信号通路。