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

Abstract

BackgroundParthenolide (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.MethodsLung 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.ResultsParthenolide (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.ConclusionWe 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.

Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle/desmoplastic melanomas

“…Activity of the chemokine receptor CXCL12–CXCR4 signalling pathway has been shown to mediate tumour cell proliferation, survival and migration in both melanoma cell lines and MPNSTs . Targeted blockade of the CXCL12–CXCR4 signalling pathway has been shown to inhibit some cancer cell lines . In our study, we found high‐level CXCR4 expression in SDMs (50%) and MPNSTs (82%), but without significant increases in CXCL12 expression, suggesting that paracrine rather than autocrine activation occurs in both entities.…”

Effect of parthenolide on growth and apoptosis regulatory genes of human cancer cell lines

“…Active caspase-3 has a variety of functions including activation of a latent cytosolic endonuclease, caspase-activated deoxyribonuclease that cleaves DNA into oligonucleosomal fragments (Fahy et al, 1999;Janicke et al, 1998). These findings can be correlated with a recent report in which parthenolide induced cleavage of apoptotic proteins, such as, caspase-8, -9, -3 and PARP1 in lung cancer cells, have been given and suggested that apoptosis was trigged after parthenolide exposure (Zhao et al, 2014). However, the present study reports the consequences of apoptosis as a DNA fragmentation in the parthenolidetreated SiHa and MCF-7 cells for the first time ( Figure 6).…”

Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death

“…Notably, 9 of the 18 genes were associated with neoplasms in their annotations. Examples include TNFRSF10B, inducing apoptosis in various solid tumors, [15][16][17][18][19] PTPN13 being upregulated in pancreatic cancer and Ewing sarcoma, 20,21 or IER3 and CCR4 that have a role in myelodysplastic syndromes and lymphoma, respectively. 22,23 In addition, TP63 contributes to tumorigenesis in several cancers.…”