Colon cancer cells expressing cell surface GRP78 as a marker for reduced tumorigenicity

Hardy, Britta; Raiter, Annat; Yakimov, Maxim; Vilkin, Alex; Niv, Yaron

doi:10.1007/s13402-012-0094-4

Cited by 22 publications

(25 citation statements)

References 36 publications

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“…These results confirm similar findings in head and neck cancer (21), but differ from a study showing that GRP78+ colon cancer cells exhibit reduced tumorigenicity compared to GRP78− cells (44). We attribute differences between these studies to the fact that our work, but not the study of Hardy et al, excluded dead cells during sorting.…”

Section: Discussionsupporting

confidence: 81%

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

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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.

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Section: Discussionsupporting

confidence: 81%

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

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“…Our results were consistent with previous studies showing that the ER chaperone GRP78 expression contributes to in vitro and in vivo antiapoptotic effects and chemotherapy resistance in many cancers (Booth et al 2012;Chang et al 2012;Hardy et al 2012;Jin et al 2012;Lee 2007). For example, levels of GRP78 in human gastric cancer cells are strongly correlated with taxane-based therapeutic resistance and recurrence of the disease (Yang et al 2014).…”

Section: Discussionsupporting

confidence: 92%

GRP78 regulates sensitivity of human colorectal cancer cells to DNA targeting agents

et al. 2014

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This study was carried out to investigate the activation status of unfolded protein response (UPR) in colorectal cancer (CRC) and its contribution to CRC resistance to chemotherapy-induced apoptosis. Chemotherapy-induced apoptosis was assessed by the propidium iodide method. Activation of UPR was evaluated in CRC cell lines using immunoblotting technique and in CRC tissues using immunohistochemistry. Findings of the present study revealed that the UPR is constitutively activated in CRC cell lines and CRC tissues isolated from patients, as evidenced by relatively high levels of the 78-kDa glucose-regulated protein (GRP78) and spliced X-box-binding protein 1 mRNA in tissue samples. In addition, CRC cell lines differentially responded to clinically relevant DNA-targeting agents including cisplatin, and 5-flourouracil. Moreover, the levels of GRP78 were inversely associated with sensitivity of CRC cells to chemotherapy-induced apoptosis. Inhibition of GRP78 by siRNA resulted in increased sensitivity of CRC cells to chemotherapeutic agents. Collectively, current results appear to provide novel insights into the role of UPR in determining sensitivity of CRC cells to chemotherapeutic agents and might have important implications for personalized CRC treatment.

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“…GRP78 is overexpressed in colon cancer (13,39) and prostate cancer (9). Our studies showed overexpression of GRP78 in pancreatic cancer cell lines and in tumor compared with normal ductal cells (Fig.…”

Section: Triptolide Induces Er Stress In Pancreatic Cancer Cells Via mentioning

confidence: 53%

“…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. 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,…”

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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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Colon cancer cells expressing cell surface GRP78 as a marker for reduced tumorigenicity

Abstract: This study demonstrates the significance of cell surface GRP78 in colon cancer, which may be used as a marker for reduced tumorigenicity.

Cited by 22 publications

References 36 publications

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

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

GRP78 regulates sensitivity of human colorectal cancer cells to DNA targeting agents

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

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