Triptolide-induced Cell Death in Pancreatic Cancer Is Mediated by O-GlcNAc Modification of Transcription Factor Sp1

Banerjee, Sulagna; Sangwan, Veena; McGinn, Olivia; Chugh, Rohit; Dudeja, Vikas; Vickers, Selwyn M.; Saluja, Ashok K.

doi:10.1074/jbc.m113.500983

Cited by 99 publications

(72 citation statements)

References 37 publications

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“…Our more recent study explored this further and showed that triptolide inhibits the transcription factor Sp1, which is upstream of a number of signaling pathways (4). This study further shows that HSF1, the transcription factor for HSP70, and NF-B, the transcription factor for a number of ER stress genes including GRP78, are regulated by Sp1.…”

Section: Discussionmentioning

confidence: 96%

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

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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...

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Section: Discussionmentioning

confidence: 96%

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

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“…Stabach et al proved that overexpression of AP2α could alter the transcriptional activity and stability of p53 in tumor tissue [43]. Besides, the nuclear localization of SP1 and its DNA binding activity could be suppressed by the inhibition of O-GlcNAc transferase, and then functioned in the cell death of pancreatic cancer [44]. Also, SP1 was a key modulator of p53-mediated apoptosis in cell apoptosis [45].…”

Section: Discussionmentioning

confidence: 97%

Identification of Key Genes Associated with Colorectal Cancer Based on the Transcriptional Network

Chen

Li²,

Niu

et al. 2015

Pathol. Oncol. Res.

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Colorectal cancer (CRC) is among the most lethal human cancers, but the mechanism of the cancer is still unclear enough. We aimed to explore the key genes in CRC progression. The gene expression profile (GSE4183) of CRC was obtained from Gene Expression Omnibus database which included 8 normal samples, 15 adenoma samples, 15 CRC samples and 15 inflammatory bowel disease (IBD) samples. Thereinto, 8 normal, 15 adenoma, and 15 CRC samples were chosen for our research. The differentially expressed genes (DEGs) in normal vs. adenoma, normal vs. CRC, and adenoma vs. CRC, were identified using the Wilcoxon test method in R respectively. The interactive network of DEGs was constructed to select the significant modules using the Pearson's correlation. Meanwhile, transcriptional network of DEGs was also constructed using the g: Profiler. Totally, 2,741 DEGs in normal vs. adenoma, 1,484 DEGs in normal vs. CRC, and 396 DEGs in adenoma vs. CRC were identified. Moreover, function analysis of DEGs in each group showed FcR-mediated phagocytosis pathway in module 1, cardiac muscle contraction pathway in module 6, and Jak-STAT signaling pathway in module 19 were also enriched. Furthermore, MZF1 and AP2 were the transcription factor in module 6, with the target SP1, while SP1 was also a transcription in module 20. DEGs like NCF1, AKT, SP1, AP2, MZF1, and TPM might be used as specific biomarkers in CRC development. Therapy targeting on the functions of these key genes might provide novel perspective for CRC treatment.

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“…Triptolide supresses the proliferation of prostate cancer cells by inhibition of expression of SUMO-specific protease 1 (7). Triptolide induces the apoptosis of pancreatic tumor cells by decreasing the expression of O-GlcNac transferase to alter the distribution of transcription factor specificity protein 1 (8). However, it is not clear if triptolide can be used to treat osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

Triptolide reduces the viability of osteosarcoma cells by reducing MKP-1 and Hsp70 expression

Zhao

Jiang

Wang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Osteosarcoma is the most common type of malignant bone tumor found in adolescents and young adults. The aim of the present study was to determine whether triptolide, a diterpene epoxide extracted from the Tripterygium plant, was able effectively decrease the viability of osteosarcoma cells. The underlying molecular mechanisms are also investigated. The human osteosarcoma cell lines U-2 OS and MG-63 were used in this study. The U-2 OS and MG-63 cells were treated with 0, 5, 10, 25 or 50 nM triptolide. Cells treated with dimethyl sulfoxide only were used as the no drug treatment control. A commercial MTT kit was used to determine the effects of triptolide on cells. Mitogen-activated protein kinase phosphatase-1 (MKP-1) is frequently overexpressed in tumor tissues, possibly related to the failure of a number of chemotherapeutics. Heat shock protein 70 (Hsp70) is a chaperone molecule that is able to increase drug resistance. The protein expression levels of MKP-1 and Hsp70 were determined using western blot analysis. The results indicate that triptolide effectively reduced the viability of the osteosarcoma cells. Furthermore, triptolide was found to effectively reduce MKP-1 expression and Hsp70 levels. Further analysis showed that triptolide reduced MKP-1 mRNA expression in the U-2 OS and MG-63 cells. Triptolide reduced Hsp70 mRNA expression levels in U-2 OS and MG-63 cells. These results suggest that triptolide effectively decreases the viability of osteosarcoma cells. These effects may be associated with the decreased expression of MKP-1 and Hsp70 levels. These results suggest that triptolide may be used in the treatments of osteosarcoma.

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Triptolide-induced Cell Death in Pancreatic Cancer Is Mediated by O-GlcNAc Modification of Transcription Factor Sp1

Cited by 99 publications

References 37 publications

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

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

Identification of Key Genes Associated with Colorectal Cancer Based on the Transcriptional Network

Triptolide reduces the viability of osteosarcoma cells by reducing MKP-1 and Hsp70 expression

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