Overexpression of GRP78 Is Associated With Malignant Transformation in Epithelial Ovarian Tumors

Huang, Lee Wen; Lin, Ching Yu; Lee, Chin Cheng; Liu, Tsan Zon; Jeng, Cherng Jye

doi:10.1097/pai.0b013e3182434113

Cited by 31 publications

(27 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, GRP78, the most important marker of UPR, has been identified as a survival factor for rescuing cells from cell death and overexpression of GRP78 has been reported to be associated with poor prognosis in a number of malignant tumors (13,14). Nevertheless, the role of GRP78 in regulating the proliferation and growth of hypopharyngeal carcinoma cells under severe hypoxia remains to be unveiled.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of glucose-regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia

Song

et al. 2013

Oncology Letters

View full text Add to dashboard Cite

Hypoxia renders tumor cells with reduced sensitivity and increased resistance to chemotherapeutic agents. One of the possible mechanisms underlying this unfavorable status is activation of the unfolded protein response (UPR) under hypoxic conditions, due to the upregulation of glucose-regulated protein 78 (GRP78) expression. GRP78, an endoplasmic reticulum chaperone protein and a key regulator of the UPR, has been reported to be overexpressed in various types of cancer. However, the role of GRP78 in regulating the cell growth and apoptosis of hypopharyngeal carcinoma cells, with regard to the severity of hypoxia, remains unclear. Therefore, the aim of the present study was to investigate whether, and under what circumstances, GRP78 is associated with hypoxia-induced chemoresistance in hypopharyngeal carcinoma. For this purpose, cells from the FaDu human hypopharyngeal carcinoma cell line were cultured under normoxic and hypoxic conditions for different time periods. No significant changes in GRP78 and C/EBP homology protein (CHOP) protein expression levels were revealed under moderately hypoxic conditions (oxygen concentration, 1%), but these levels were changed over time under severely hypoxic conditions (oxygen concentration, <0.02%). This indicated that severe hypoxia, rather than moderate hypoxia, leads to UPR activation in hypopharyngeal carcinoma cells. Knockdown of GRP78 with short hairpin RNA inhibited cell proliferation and promoted apoptosis under severely hypoxic conditions, even with cisplatin treatment, indicating that GRP78 confers FaDu cells resistant to chemotherapy in response to severe hypoxia. Furthermore, knockdown of GRP78 resulted in a significant increase in CHOP and Bax expression levels and a decrease in Bcl-2 expression levels with simultaneous increase in the levels of apoptosis under severely hypoxic conditions. It was concluded that severe hypoxia leads to UPR activation and elevation of GRP78 expression, promoting cell survival and inducing chemoresistance. Silencing of GRP78 may block the pro-survival arm of UPR, simultaneously promoting proapoptotic signaling through induction of CHOP. Downregulation of GRP78 may be a promising strategy for overcoming the resistance of hypopharyngeal cancer to chemotherapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Knockdown of glucose-regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia

Song

et al. 2013

Oncology Letters

View full text Add to dashboard Cite

show abstract

“…A key player in this process is the survival protein GRP78. GRP78 is overexpressed in many human cancers, where it mediates tumor growth by enhancing proliferation and protecting against apoptosis (16,21,41). Our findings of an increased expression of GRP78 not only in the human pancreatic cancer cell lines, but also in the human pancreatic cancer tissue samples (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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

“…Overexpression of GRP78 correlates with malignant transformation in epithelial ovarian tumor cells (19), while inducible knockout of GRP78 in the hematopoietic system suppresses Pten-null leukemogenesis (20). Mem GRP78 is associated with increased cancer stemness in head and neck cancer (21).…”

Section: Introductionmentioning

confidence: 99%

Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78

Bachelder

Kennedy

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Ovarian cancer patients are generally diagnosed at FIGO (International Federation of Gynecology and Obstetrics) stage III/IV, when ascites is common. The volume of ascites correlates positively with the extent of metastasis and negatively with prognosis. Membrane GRP78, a stress-inducible endoplasmic reticulum chaperone that is also expressed on the plasma membrane (memGRP78) of aggressive cancer cells, plays a crucial role in the embryonic stem cell maintenance. We studied ascites effects on ovarian cancer stem-like cells using a syngeneic mouse model. Our study demonstrates that ascites-derived tumor cells from mice injected intraperitoneally with murine ovarian cancer cells (ID8) express increased memGRP78 levels compared to ID8 cells from normal culture. We hypothesized that these ascites associated memGRP78+ cells are cancer stem-like cells (CSC). Supporting this hypothesis, we show that memGRP78+ cells isolated from murine ascites exhibit increased sphere forming and tumor initiating abilities compared to memGRP78− cells. When the tumor microenvironment is recapitulated by adding ascites fluid to cell culture, ID8 cells express more memGRP78 and increased self-renewing ability compared to those cultured in medium alone. Moreover, compared to their counterparts cultured in normal medium, ID8 cells cultured in ascites, or isolated from ascites, show increased stem cell marker expression. Antibodies directed against the carboxy-terminal domain of GRP78: 1) reduce self-renewing ability of murine and human ovarian cancer cells pre-incubated with ascites and 2) suppress a GSK3α-AKT/SNAI1 signaling axis in these cells. Based on these data, we suggest that memGRP78 is a logical therapeutic target for late stage ovarian cancer.

show abstract

Overexpression of GRP78 Is Associated With Malignant Transformation in Epithelial Ovarian Tumors

Abstract: The present study suggests that GRP78 plays a significant role in malignant transformation of epithelial ovarian tumors and may represent an important biomarker for EOCs.

Cited by 31 publications

References 17 publications

Knockdown of glucose-regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia

Knockdown of glucose-regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia

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

Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78

Contact Info

Product

Resources

About