Unfolded protein response activation contributes to chemoresistance in hepatocellular carcinoma

Al-Rawashdeh, Feras; Scriven, Peter; Cameron, Ian C.; Vergani, Patricia; Wyld, Lynda

doi:10.1097/meg.0b013e3283378405

Cited by 69 publications

(56 citation statements)

References 45 publications

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“…GRP78/Bip, an ER stress chaperone, was shown to help protein folding and transport during ER stress-induced unfolded protein response. External stress could induce a high expression of GRP78/Bip to maintain ER homeostasis and cell survival (32,33). In the present study, the levels of GRP78/Bip, phosphorylated PERK and Bcl-2 in the HepG2/IR cells were significantly increased, which was consistent with previous observations.…”

Section: Discussionmentioning

confidence: 99%

Insulin resistance contributes to multidrug resistance in HepG2 cells via activation of the PERK signaling pathway and upregulation of Bcl-2 and P-gp

Cheng

et al. 2016

Oncology Reports

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Section: Discussionmentioning

confidence: 99%

Insulin resistance contributes to multidrug resistance in HepG2 cells via activation of the PERK signaling pathway and upregulation of Bcl-2 and P-gp

Cheng

et al. 2016

Oncology Reports

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“…Although GRP78 expression is maintained at low basal levels in major adult organs, it has often been found to be upregulated in cancer cells (2,16,26,34,36). Studies have shown that although the majority of GRP78 resides in the ER lumen, a fraction of it exists as an ER transmembrane protein, with its NH 2 portion in the cytosol.…”

mentioning

confidence: 99%

“…This can directly bind and inhibit the activity of proapoptotic effectors, such as caspase-7 and the BH3-only proapoptotic protein BIK and its downstream target BAX (13,22). It is intriguing that increased expression of GRP78, which is a mechanism that tolerates a low level of chronic ER stress to thrive under suboptimal conditions, not only causes prosurvival robustness but also confers increased chemoresistance (2,26). Hence, to decrease the ability of tumors to survive and proliferate under suboptimal conditions, it would be highly desirable to block GRP78 expression.…”

mentioning

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

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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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“…Also in the liver, Grp78 and the ER stress response seems to be pro-oncogenic: The ER stress response has been implicated in hepatocarcinogenesis [43] and in resistance of hepatocellular carcinoma cells against drugs such as camptothecin, etoposide and doxorubicin [44,45]. Since a few years, Sorafenib has been successfully applied in the treatment of patients with advanced HCC [46,47].…”

Section: Page 20 Of 40mentioning

confidence: 99%

Oncostatin M up-regulates the ER chaperone Grp78/BiP in liver cells

Vollmer

Haan

Behrmann

2010

Biochemical Pharmacology

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International audienceOSM, a cytokine of the IL-6 type cytokine family, regulates inflammatory processes (acute phase, tissue remodeling, angiogenesis), cell differentiation and proliferation. Inflammation is discussed to favor carcinogenesis and the inflammatory cytokine OSM was lately described to upregulate HIF-1α, whose upregulation is also observed in many cancers. In this study we demonstrate that OSM, and to a lesser degree by IL-6, induces the expression of Grp78/BiP, an ER chaperone associated with tumor development and poor prognosis in cancer. In contrast, IFN-γ or TNF-α.had no effect on Grp78 expression. The up-regulation seems to be specific to liver cells, as it occurs in hepatocytes and hepatoma cells but not in prostate, melanoma, breast or kidney cells. OSM does not lead to up-regulation of Grp94, enhanced XBP-1 mRNA splicing or phosphorylation of eIF2α, indicating that it is not associated to a general ER stress response. Analysis of the underlying mechanism showed that Grp78 is up-regulated by transcriptional processes which are to the greater part, though not completely, dependent on MEK/Erk activation

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Unfolded protein response activation contributes to chemoresistance in hepatocellular carcinoma

Abstract: The UPR is activated in HCCs and confers resistance to chemotherapy in vitro. UPR activation may contribute to HCC chemoresistance.

Cited by 69 publications

References 45 publications

Insulin resistance contributes to multidrug resistance in HepG2 cells via activation of the PERK signaling pathway and upregulation of Bcl-2 and P-gp

Insulin resistance contributes to multidrug resistance in HepG2 cells via activation of the PERK signaling pathway and upregulation of Bcl-2 and P-gp

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

Oncostatin M up-regulates the ER chaperone Grp78/BiP in liver cells

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