Triptolide-mediated cell death in neuroblastoma occurs by both apoptosis and autophagy pathways and results in inhibition of nuclear factor–kappa B activity

Krosch, Tara C.K.; Sangwan, Veena; Banerjee, Sulagna; Mujumdar, Nameeta; Dudeja, Vikas; Saluja, Ashok K.; Vickers, Selwyn M.

doi:10.1016/j.amjsurg.2013.01.008

Cited by 51 publications

(36 citation statements)

References 28 publications

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“…Triptolide is also effective against a number of additional malignancies, including cholangiocarcinoma (23), gastric cancer (24), osteosarcoma (25) and neuroblastoma (26,27). Triptolide affects a number of prosurvival pathways in cancer cells.…”

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confidence: 99%

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

Banerjee

Sangwan

McGinn

et al. 2013

Journal of Biological Chemistry

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Background: Preclinical evaluation of triptolide shows pancreatic tumor regression in animal models. Results: Triptolide deregulates glycosylation of Sp1, leading to its decreased activity and causing pancreatic cancer cell death associated with down-regulating HSP70. Conclusion: Triptolide down-regulation of HSP70 is associated with inhibition of Sp1 activity in pancreatic cancer. Significance: This mechanism is of relevance, as its water-soluble prodrug, Minnelide, is currently under Phase 1 clinical trial.

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

Banerjee

Sangwan

McGinn

et al. 2013

Journal of Biological Chemistry

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“…We and others have shown that triptolide inhibits the growth of a number of cancers in nude mice (3,6,8,19). Our previous study showed that triptolide activates differential cell death pathways in different pancreatic cancer cell lines: apoptotic cell death in the primary cell lines MIA PaCa-2 and Capan-1 and autophagy-associated cell death in the metastatic cell lines S2-013, S2-VP10, and Hs766T (27).…”

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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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“…25–27 Since all cell lines tested are of human origin, the ability of triptolide to reduce tumor burden in vivo was analyzed in immune depleted animals. We therefore tested triptolide as a therapy against KPC cells derived from KPC tumors, which are derived from immune-competent animals.…”

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confidence: 99%

Primary and Liver Metastasis–Derived Cell Lines From KrasG12D; Trp53R172H; Pdx-1 Cre Animals Undergo Apoptosis in Response to Triptolide

et al. 2015

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Objectives Pancreatic cancer has a five year survival rate of less than 5%, partly due to limited chemotherapeutic options, thereby highlighting the need for novel therapies. Triptolide, a diterpene triepoxide derived from a Chinese herb has shown great promise in preclinical testing against pancreatic cancer using immune compromised animals. Results In this study, we tested the ability of triptolide to induce cell death in cell lines derived from a primary tumor and adjacent liver metastases of immuno-competent animals (KRasG12D; Trp52R172H; Pdx-1 Cre (KPC)). Both cell lines were more aggressive in their ability to form tumors when compared to other pancreatic cancer cell lines, and showed constitutive activation of the NFkB pathway. Triptolide induced apoptotic cell death in both cell lines, as evidenced by decreased cell viability and increased caspase 3/7 activity, Annexin V positivity, and increased TUNEL positivity in tumors from KPC animals treated with Minnelide. Additionally, triptolide decreased levels of HSP70, its transcription factor HSF1, and the anti-apoptotic proteins Bcl-xL, Bcl-2 and Mcl-1, known to be up-regulated in pancreatic cancer. Conclusion The ability of triptolide to cause cell death in cell lines derived from immune-competent animals further validates its potential as a novel agent against pancreatic cancer.

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Triptolide-mediated cell death in neuroblastoma occurs by both apoptosis and autophagy pathways and results in inhibition of nuclear factor–kappa B activity

Abstract: Triptolide treatment induces cell death in neuroblastoma by different mechanisms with multiple pathways targeted. Triptolide may serve a potential chemotherapeutic role in advanced cases of neuroblastoma.

Cited by 51 publications

References 28 publications

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

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

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

Primary and Liver Metastasis–Derived Cell Lines From KrasG12D; Trp53R172H; Pdx-1 Cre Animals Undergo Apoptosis in Response to Triptolide

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