Triptolide induces autophagy and apoptosis through ERK activation in human breast cancer MCF‑7 cells

Abstract

Abstract.To investigate the effects of triptolide (TPI) on proliferation, autophagy and death in human breast cancer MCF-7 cells, and to elucidate the associated molecular mechanisms, intracellular alterations were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays. The results of the MTT assay revealed that TPI significantly reduced the MCF-7 cell survival rate when the concentration was >10 nmol/l. TPI activated a caspase cascade reaction by regulating Bcl-2-associated X protein (Bax), caspase-3 and B-cell lymphoma 2 expression, and promoted programmed cell death via the mitochondrial pathway. The results demonstrated that TPI significantly reduced the cell proliferation rate and viability in a time-and dose-dependent manner, which was confirmed by western blotting and immunofluorescent staining. TPI induced autophagy and influenced p38 mitogen-activated protein kinases, extracellular signal-regulated kinase (Erk)1/2, and mammalian target of rapamycin (mTOR) phosphorylation, which resulted in apoptosis. When cells were treated with a combination of TPI and the Erk1/2 inhibitor U0126, the downregulation of P62 and upregulation of Bax were inhibited, which demonstrated that the inhibition of Erk1/2 reversed the autophagy changes induced by TPI. The results indicated that Erk1/2 activation may be a novel mechanism by which TPI induces autophagy and apoptosis in MCF-7 breast cancer cells. In conclusion, TPI affects the proliferation and apoptosis of MCF-7 cells, potentially via autophagy and p38/Erk/mTOR phosphorylation. The present study offers a novel view of the mechanisms by which TPI regulates cell death.

Inhibition of extracellular signal‐regulated kinase potentiates the apoptotic and antimetastatic effects of cyclin‐dependent kinase inhibitors on metastatic DU145 and PC3 prostate cancer cells

“…Although the mitochondria-mediated apoptotic induction by CDK inhibitors was shown in previous studies on prostate, breast, and colon cancer cells, the association of MAPK signaling in purvalanol-induced apoptosis was not clear. 22 In accordance with previous studies, we suggested that fine-tuning regulation of MAPKs in the CDK inhibitorinduced apoptosis mechanism is a promising target in the therapy of prostate cancer cells with high metastatic profile. 19 Knockeart et al 20 showed F I G U R E 5 MAPK inhibition further induced the CDK inhibitors-reduced cell survival axis and EMT related protein levels.…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…It induces mitochondrial apoptotic pathway to mediate apoptosis in Burkitt's lumphoma Raji, NAMALWA and Daudi cells, and inhibits tumor growth in Daudi xenograft mice [432], and inhibits cell proliferation through microRNA-181a up-regulation in human neuroblastoma SH-SY5Y cells [433]. Moreover, triptolide induces autophagy to induce apoptosis and inhibit angiogenesis in human osteosarcoma MG63 cells, and breast cancer MCF-7 cells [431,434]. In contrast, triptolide induces protective autophagy through calcium (Ca 2+ )/calmodulin-dependent protein kinase kinase β (CaMKKβ)-AMPK pathway in human prostate cancer PC-3, LNCaP and C4-2 cells, and through Akt/ mTOR down-regulation in human cervical SiHa cells [420,435].…”

“…Moreover, ERK is also shown to be important in mediating triptolide-induced anti-cancer activities. Triptolide induces apoptosis through ERK activation in human breast cancer MDA-MB-231 and MCF-7 cells [434,442], and ERK activation leads to caspase activation, Bax up-regulation and Bcl-xL down-regulation [442]. On the other hand, it can also inhibit metastasis through ERK down-regulation in esophageal squamous cell cancer KYSE180 and KYSE150 cells, and murine melanoma B16F10 cells [443,444].…”

Triptolide-induced apoptosis in non-small cell lung cancer via a novel miR204-5p/Caveolin-1/Akt-mediated pathway

“…More recently, studies by Liu and coworkers [32] demonstrated that knockdown of CAV-1 in A549 cells enhanced cisplatin-triggered cancer death. Because of the growth inhibition and associated apoptotic effects of TL in a wide variety of epithelial and hematological cancer cell lines [5][6][7][8][9][10][11], including NSCLC cells [4,12], we investigated the potential changes in CAV-1 mRNA/ protein expression following TL treatment in A549 and NCI-H460 lung cancer cells.…”