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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Journal of Experimental & Clinical Cancer Research 1/2014

Parthenolide induces apoptosis via TNFRSF10B and PMAIP1 pathways in human lung cancer cells

Zeitschrift:
Journal of Experimental & Clinical Cancer Research > Ausgabe 1/2014
Autoren:
Xiaofei Zhao, Xiangguo Liu, Ling Su
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1756-9966-33-3) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

LS and XL designed research; XZ and LS performed research; XZ and LS analyzed data; XZ, XL and LS wrote the paper. All authors read and approved the final manuscript.

Abstract

Background

Parthenolide (PTL) is a sesquiterpene lactone which can induce apoptosis in cancer cells and eradicate cancer stem cells such as leukemia stem cells, prostate tumor-initiating cells and so on. However, the mechanism remains largely unclear.

Methods

Lung cancer cells were treated with parthenolide and the cell lysates were prepared to detect the given proteins by Western Blot analysis, and the cell survival was assayed by SRB and MTT assay. Cell cycle was evaluated by DNA flow cytometry analysis. TNFRSF10B, PMAIP1, ATF4 and DDIT3 genes were knocked down by siRNA technique. Apoptosis was evaluated by using Annexin V-FITC/PI staining and flow cytometry analysis.

Results

Parthenolide (PTL) induces apoptosis and cell cycle arrest in human lung cancer cells. Moreover, PTL treatment in NSCLC cells increases expression of TNFRSF10B/DR5 and PMAIP1/NOXA. Silencing of TNFRSF10B or PMAIP1 or overexpression of CFLAR /c-FLIP (long form) could protect cells from PTL-induced apoptosis. Furthermore, PTL could increase the levels of endoplasmic reticulum stress hallmarks such as ERN1, HSPA5, p-EIF2A, ATF4 and DDIT3. Knockdown of ATF4 and DDIT3 abrogated PTL-induced apoptosis, which suggested that PTL induced apoptosis in NSCLC cells through activation of endoplasmic reticulum stress pathway. More importantly, we found that ATF4, DDIT3, TNFRSF10B and PMAIP1 were up-regulated more intensively, while CFLAR and MCL1 were down-regulated more dramatically by PTL in A549/shCDH1 cells than that in control cells, suggesting that PTL preferred to kill cancer stem cell-like cells by activating more intensive ER stress response in cancer stem cell-like cells.

Conclusion

We showed that parthenolide not only triggered extrinsic apoptosis by up-regulating TNFRSF10B and down-regulating CFLAR, but also induced intrinsic apoptosis through increasing the expression of PMAIP1 and decreasing the level of MCL1 in NSCLC cells. In addition, parthenolide triggered stronger ER stress response in cancer stem cell-like cells which leads to its preference in apoptotic induction. In summary, PTL induces apoptosis in NSCLC cells by activating endoplasmic reticulum stress response.
Zusatzmaterial
Additional file 1: Figure S1: Parthenolide induces cell cycle arrest in NSCLC cell lines. A549 (A) and H1792 (B) cells were treated with different concentrations of PTL for 24 hours. After treatment, the cells were harvested for cell cycle assays. Figure S2. Cancer stem cell makers are up-regulated in A549/shCDH1 cells. The expression level of SOX2 and POU5F1 were detected in A549/shCtrl and A549/shCDH1 cells by Western Blot assay. (PPT 246 KB)
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Literatur
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