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Induction of Apoptosis in Human Pancreatic Cancer Stem Cells by the Endoplasmic Reticulum-Targeted Alkylphospholipid Analog Edelfosine and Potentiation by Autophagy Inhibition

內(nèi)質(zhì)網(wǎng)靶向烷基磷脂類似物艾德爾福辛誘導(dǎo)人胰腺癌干細(xì)胞凋亡和自噬抑制增強作用

Pancreatic cancer remains an incurable cancer with a gloomy prognosis and a median survival of months since the time of diagnosis. Disappointingly, no significant improvement in clinical outcomes has been achieved for the last fifty years. Cancer stem cells (CSCs) are suggested to be critical and responsible for tumor development, drug resistance and cancer relapse, therefore, an effective antitumor therapy against pancreatic cancer should deal with pancreatic CSCs. Here, we found that the alkylphospholipid analog edelfosine induces apoptosis in pancreatic CD44+CD24+EpCAM+ CSCs through its accumulation in the endoplasmic reticulum, leading to sustained endoplasmic reticulum stress and cell death. Edelfosine was effective against primary cultures from pancreatic cancer patients and their corresponding pancreatic CSCs. Autophagy inhibition potentiated the proapoptotic action of edelfosine in pancreatic CSCs. Thus, endoplasmic reticulum targeting and its combination with autophagy inhibitors could open a new framework in pancreatic cancer chemotherapy, directly involving pancreatic CSCs.

胰腺癌仍然是一種無法治愈的癌癥，預(yù)后不佳，自診斷以來的中位生存期為數(shù)月。令人失望的是，在過去的五十年里，臨床結(jié)果沒有顯著改善。癌癥干細(xì)胞 (CSCs) 被認(rèn)為是腫瘤發(fā)展、耐藥性和癌癥復(fù)發(fā)的關(guān)鍵和原因，因此，針對胰腺癌的有效抗腫瘤治療應(yīng)處理胰腺 CSCs。在這里，我們發(fā)現(xiàn)烷基磷脂類似物 edelfosine 在胰腺 CD44 + CD24 + EpCAM +中誘導(dǎo)細(xì)胞凋亡CSCs通過其在內(nèi)質(zhì)網(wǎng)中的積累，導(dǎo)致持續(xù)的內(nèi)質(zhì)網(wǎng)應(yīng)激和細(xì)胞死亡。Edelfosine 對胰腺癌患者及其相應(yīng)的胰腺 CSC 的原代培養(yǎng)物有效。自噬抑制增強了依地福辛在胰腺 CSC 中的促凋亡作用。因此，內(nèi)質(zhì)網(wǎng)靶向及其與自噬抑制劑的組合可以在胰腺癌化療中開辟一個新的框架，直接涉及胰腺 CSC。

細(xì)胞工廠

Pancreatic cancer is one of the most lethal malignancies with a poor and gloomy prognosis and the highest mortality-to-incidence ratio. Pancreatic cancer remains an incurable malignancy, and current therapies are ineffective. We isolated cancer stem cells (CSCs) from the human PANC-1 pancreatic cancer cell line as CD44+CD24+EpCAM+ cells. These CSCs form pancreatic cancer spheres or spheroids and develop tumors in SCID mice after subcutaneous injection of as few as 100 cells per mouse. Here, we found that the alkylphospholipid analog edelfosine inhibited CSC pancreatic cancer spheroid formation and induced cell death, as assessed by an increase in the percentage of cells in the sub-G0/G1 region by means of flow cytometry, indicative of DNA breakdown and apoptosis. This correlated with an increase in caspase-3 activity and PARP breakdown, as a major substrate of caspase-3, following PANC-1 CSC treatment with edelfosine. The antitumor ether lipid edelfosine colocalized with the endoplasmic reticulum in both PANC-1 cells as well as PANC-1 CSCs by using a fluorescent edelfosine analog, and induced an endoplasmic reticulum stress response in both PANC-1 cells and PANC-1 CSCs, with a potent CHOP/GADD153 upregulation. Edelfosine elicited a strong autophagy response in both PANC-1 cells and PANC-1 CSCs, and preincubation of CSCs with autophagy inhibitors, chloroquine or bafilomycin A1, enhanced edelfosine-induced apoptosis. Primary cultures from pancreatic cancer patients were sensitive to edelfosine, as well as their respective isolated CSCs. Nontumorigenic pancreatic human cell line HPNE and normal human fibroblasts were largely spared. These data suggest that pancreatic CSCs isolated from established cell lines and pancreatic cancer patients are sensitive to edelfosine through its accumulation in the endoplasmic reticulum and induction of endoplasmic reticulum stress.

細(xì)胞搖瓶

胰腺癌是最致命的惡性腫瘤之一，預(yù)后差，病死率最高。胰腺癌仍然是一種無法治愈的惡性腫瘤，目前的治療方法無效。我們從人 PANC-1 胰腺癌細(xì)胞系中分離出癌癥干細(xì)胞 (CSC)，即 CD44 + CD24 + EpCAM +細(xì)胞。這些 CSC 形成胰腺癌球體或球狀體，并在每只小鼠皮下注射少至 100 個細(xì)胞后在 SCID 小鼠中形成腫瘤。在這里，我們發(fā)現(xiàn)烷基磷脂類似物 edelfosine 抑制 CSC 胰腺癌球體的形成并誘導(dǎo)細(xì)胞死亡，這是通過 sub-G 0 /G 1中細(xì)胞百分比的增加來評估的流式細(xì)胞儀檢測區(qū)域，指示 DNA 分解和細(xì)胞凋亡。這與 caspase-3 活性和 PARP 分解的增加相關(guān)，作為 caspase-3 的主要底物，在用 edelfosine 處理 PANC-1 CSC 后。通過使用熒光edelfosine類似物，抗腫瘤醚脂質(zhì)edelfosine與PANC-1細(xì)胞和PANC-1 CSCs中的內(nèi)質(zhì)網(wǎng)共定位，并在PANC-1細(xì)胞和PANC-1 CSCs中誘導(dǎo)內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)，有效的 CHOP/GADD153 上調(diào)。Edelfosine 在 PANC-1 細(xì)胞和 PANC-1 CSCs 中引起強烈的自噬反應(yīng)，并且 CSCs 與自噬抑制劑、氯喹或巴弗洛霉素 A1 的預(yù)孵育增強了 edelfosine 誘導(dǎo)的細(xì)胞凋亡。胰腺癌患者的原代培養(yǎng)物對依地福辛敏感，以及它們各自孤立的 CSC。非致瘤性胰腺人細(xì)胞系 HPNE 和正常人成纖維細(xì)胞在很大程度上幸免于難。這些數(shù)據(jù)表明，從已建立的細(xì)胞系和胰腺癌患者中分離的胰腺 CSC 通過其在內(nèi)質(zhì)網(wǎng)中的積累和內(nèi)質(zhì)網(wǎng)應(yīng)激的誘導(dǎo)而對依地福辛敏感。

The antitumor ether lipid edelfosine induces apoptosis in CD44+CD24+EpCAM+ pancreatic cancer stem cells (CSCs) and blocks the formation of pancreatic CSC spheroids, derived from the established human pancreatic cancer cell lines as well as from pancreatic cancer patient-derived primary cultures. Edelfosine accumulates in the endoplasmic reticulum (ER) of pancreatic CSCs, leading to persistent ER stress and eventually to cell death. Autophagy is triggered in CSCs as a protective signal to ER stress following edelfosine treatment, and thereby the combination of endoplasmic reticulum targeting with the action of autophagy inhibitors potentiates the proapoptotic activity of edelfosine against CSCs, and represents a promising approach to pancreatic cancer therapy. In addition, orally administered edelfosine lacks significant toxicity, and hence further studies are warranted to unveil its potential as a promising new approach in pancreatic cancer chemotherapy.

PETG血清培養(yǎng)基瓶

抗腫瘤醚脂質(zhì)依地福辛誘導(dǎo) CD44 + CD24 + EpCAM +細(xì)胞凋亡胰腺癌干細(xì)胞 (CSC) 并阻止胰腺 CSC 球狀體的形成，這些球狀體來源于已建立的人類胰腺癌細(xì)胞系以及胰腺癌患者來源的原代培養(yǎng)物。Edelfosine 在胰腺 CSC 的內(nèi)質(zhì)網(wǎng) (ER) 中積累，導(dǎo)致持續(xù)的 ER 應(yīng)激并最終導(dǎo)致細(xì)胞死亡。自噬在 CSCs 中被觸發(fā)，作為 edelfosine 治療后 ER 應(yīng)激的保護信號，因此內(nèi)質(zhì)網(wǎng)靶向與自噬抑制劑作用的結(jié)合增強了 edelfosine 對 CSCs 的促凋亡活性，并代表了一種有前途的胰腺癌治療方法。此外，口服依地福辛沒有明顯的毒性。

Keywords: pancreatic cancer stem cell,pancreatic cancer spheroid,endoplasmic reticulum, endoplasmic reticulum targeting,autophagy, pancreatic cancer, primary cultures from pancreatic cancer patients,alkylphospholipid analog,antitumor ether lipid,edelfosine,胰腺癌干細(xì)胞,胰腺癌球體,內(nèi)質(zhì)網(wǎng); 內(nèi)質(zhì)網(wǎng)靶向,自噬,胰腺癌,胰腺癌患者的原代培養(yǎng)物,烷基磷脂類似物,抗腫瘤醚脂,依地福辛

來源：MDPI https://www.mdpi.com/2072-6694/13/23/6124/htm