Autophagy-dependent EIF2AK3 activation compromises ursolic acid-induced apoptosis through upregulation of MCL1 in MCF-7 human breast cancer cells

Zhao, Chong; Yin, Shutao; Dong, Yinhui; Guo, Xusheng; Fan, Lihong; Ye, Min; Hu, Hongbo

doi:10.4161/auto.22805

Cited by 71 publications

(40 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overexpression of Bcl‐2 inhibited the upregulation of Beclin‐1 and followed autophagosome formation in HSFBs. Our data clearly confirmed that the UA‐induced decrease in Bcl‐2 contributed to UA‐induced Beclin‐1 activation and followed autophagosome formation, which was contradictory to a previous study in MCF‐7 and U87 cells . The discrepancy in these results may be attributed to cell type variance.…”

Section: Discussionsupporting

confidence: 59%

Inactivation of Beclin‐1‐dependent autophagy promotes ursolic acid‐induced apoptosis in hypertrophic scar fibroblasts

Cao

Wang

et al. 2017

Experimental Dermatology

View full text Add to dashboard Cite

A hypertrophic scar (HS) is caused by abnormal proliferation of dermal fibroblasts.Thus, promoting hypertrophic scar fibroblast (HSFB) apoptosis is an effective strategy for HS therapy. Ursolic acid (UA) has been widely used as an inducer of apoptosis in diverse cancers. However, whether UA plays an inhibitory role in HS formation is still unknown. In our study, UA was used to treat HSFBs and the cell viability, apoptosis, and collagen synthesis were determined by a Cell Counting Kit 8 assay, flow cytometry, and an H 3 -proline incorporation assay, respectively. Autophagy activity was detected by LC3 immunoblotting and electron microscopy, and siRNAs targeting Beclin-1 were used to inhibit autophagy. Western blotting was performed to investigate the molecular changes in HSFBs after various treatments. We found that UA inhibited col- Collectively, our study demonstrated that UA is a novel agent for inhibiting HS formation by promoting apoptosis, especially in combination with an autophagy inhibitor.Our results provide strong evidence of the application of UA in clinical HS treatment. K E Y W O R D Sapoptosis, autophagy, hypertrophic scar fibroblasts, hypertrophic scars, ursolic acid

show abstract

Section: Discussionsupporting

confidence: 59%

Inactivation of Beclin‐1‐dependent autophagy promotes ursolic acid‐induced apoptosis in hypertrophic scar fibroblasts

Cao

Wang

et al. 2017

Experimental Dermatology

View full text Add to dashboard Cite

show abstract

“…Although some reports suggest that compounds that induce sustained eIF2␣ phosphorylation provide cytoprotection in situations of ER stress (11), other reports have shown a prolonged suppression of protein synthesis, which is incompatible with cell survival and leads to autophagy (20). Moreover, involvement of the PERK-eIF2␣ axis of ER stress in apoptotic cell death has also been well documented (40). This is consistent with our current observations and our earlier finding that triptolide treatment causes a sustained increase in the levels of phosphorylated eIF2␣ and causes autophagyassociated cell death in S2-VP10 cells (Figs.…”

Section: Discussionmentioning

confidence: 99%

Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells

Mujumdar

Banerjee

Chen

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

SM, Saluja AK. Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol 306: G1011-G1020, 2014. First published April 3, 2014; doi:10.1152/ajpgi.00466.2013.-Pancreatic cancer is a devastating disease with a survival rate of Ͻ5%. Moreover, pancreatic cancer aggressiveness is closely related to high levels of prosurvival mediators, which can ultimately lead to rapid disease progression. One of the mechanisms that enables tumor cells to evade cellular stress and promote unhindered proliferation is the endoplasmic reticulum (ER) stress response. Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response (UPR). The UPR initially compensates for damage, but it eventually triggers cell death if ER dysfunction is severe or prolonged. Triptolide, a diterpene triepoxide, has been shown to be an effective compound against pancreatic cancer. Our results show that triptolide induces the UPR by activating the PKR-like ER kinase-eukaryotic initiation factor 2␣ axis and the inositol-requiring enzyme 1␣-X-box-binding protein 1 axis of the UPR and leads to chronic ER stress in pancreatic cancer. Our results further show that glucose-regulated protein 78 (GRP78), one of the major regulators of ER stress, is downregulated by triptolide, leading to cell death by apoptosis in MIA PaCa-2 cells and autophagy in S2-VP10 cells. endoplasmic reticulum stress; apoptosis; autophagy; pancreatic cancer; triptolide; glucose-regulated protein 78 PANCREATIC ADENOCARCINOMA is the fourth-leading cause of cancer-related death in the United States, with a 5-yr survival rate of Ͻ5% (17). Thus, understanding the pathobiology of pancreatic cancer is of utmost importance in developing innovative and effective therapies against it.Proper folding of secreted and transmembrane proteins occurs in the endoplasmic reticulum (ER). Many different physiological processes, highly secretory cells such as pancreatic ␤-cells, plasma B lymphocytes, and salivary glands, and pathological conditions such as hypoxia, ER Ca 2ϩ depletion, oxidative stress, viral infections, and cancer can cause an imbalance between ER protein folding load and capacity, leading to accumulation of unfolded proteins in the ER lumen, a condition known as "ER stress" (15, 31). Adaptation to ER stress is mediated by induction of the unfolded protein response (UPR), a signal transduction pathway that transmits information about protein folding status in the ER lumen to the nucleus to increase folding capacity, aiding in cell survival. The UPR involves three distinct components: 1) transcriptional induction of genes encoding ER-resident chaperones to facilitate protein folding, 2) translational attenuation to decrease the demands on the organelle, and 3) ER-associated degradation to degrade the accumulated unfolded proteins via the ubiquitin-proteasome pathway (18).In mammalian cells, the UPR is controlled by three transmembrane ER sensor...

show abstract

“…Ursolic acid (UA), a natural pentacyclic triterpene compound (Figure 1), which is widely found in medicinal plants such as holy basil, food, and other plants, exhibits anticancer potential effect in vitro and in vivo 15. It inhibited proliferation and caused apoptosis in cells of numerous cancers, including breast cancer,16 colon cancer,17 non-small cell lung cancer,18 cervical cancer,19 multiple myeloma,20 pancreatic cancer,21 melanoma,22 and prostate cancer 23. UA has been shown to prevent CCl 4 -induced hepatotoxicity and fibrosis via Nrf2/ARE pathway 24.…”

Section: Introductionmentioning

confidence: 99%

Ursolic acid sensitizes cisplatin-resistant HepG2/DDP cells to cisplatin via inhibiting Nrf2/ARE pathway

Wu¹,

Zhang

Du³

2016

DDDT

View full text Add to dashboard Cite

BackgroundCombinations of adjuvant sensitizers with anticancer drugs is a promising new strategy to reverse chemoresistance. Ursolic acid (UA) is one of the natural pentacyclic triterpene compounds known to have many pharmacological characteristics such as anti-inflammatory and anticancer properties. This study investigates whether UA can sensitize hepatocellular carcinoma cells to cisplatin.Materials and methodsCells were transfected with nuclear factor erythroid-2-related factor 2 (Nrf2) small interfering RNA and Nrf2 complementary DNA by using Lipofectin 2000. The cytotoxicity of cells was investigated by Cell Counting Kit 8 assay. Cell apoptosis, cell cycle, reactive oxygen species, and mitochondrial membrane potential were detected by flow cytometry fluorescence-activated cell sorting. The protein level of Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and heme oxygenase-1 (HO-1) was detected by Western blot analysis.ResultsThe results showed that the reverse index was 2.9- and 9.69-fold by UA of 1.125 μg/mL and 2.25 μg/mL, respectively, for cisplatin to HepG2/DDP cells. UA–cisplatin combination induced cell apoptosis and reactive oxygen species, blocked the cell cycle in G0/G1 phase, and reduced the mitochondrial membrane potential. Mechanistically, UA–cisplatin dramatically decreased the expression of Nrf2 and its downstream genes. The sensibilization of UA–cisplatin combination was diminished in Nrf2 small interfering RNA-transfected HepG2/DDP cells, as well as in Nrf2 complementary DNA-transfected HepG2/DDP cells.ConclusionThe results confirmed the sensibilization of UA on HepG2/DDP cells to cisplatin, which was possibly mediated via the Nrf2/antioxidant response element pathway.

show abstract

Autophagy-dependent EIF2AK3 activation compromises ursolic acid-induced apoptosis through upregulation of MCL1 in MCF-7 human breast cancer cells

Abstract: (2013) Autophagy-dependent EIF2AK3 activation compromises ursolic acid-induced apoptosis through upregulation of MCL1 in MCF-7 human breast cancer cells, Autophagy, 9:2,[196][197][198][199][200][201][202][203][204][205][206][207]

Cited by 71 publications

References 33 publications

Inactivation of Beclin‐1‐dependent autophagy promotes ursolic acid‐induced apoptosis in hypertrophic scar fibroblasts

Inactivation of Beclin‐1‐dependent autophagy promotes ursolic acid‐induced apoptosis in hypertrophic scar fibroblasts

Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells

Ursolic acid sensitizes cisplatin-resistant HepG2/DDP cells to cisplatin via inhibiting Nrf2/ARE pathway

Contact Info

Product

Resources

About