GRP78/BiP Inhibits Endoplasmic Reticulum BIK and Protects Human Breast Cancer Cells against Estrogen Starvation–Induced Apoptosis

Fu, Yong; Li, Jianze; Lee, Amy

doi:10.1158/0008-5472.can-06-4594

Cited by 282 publications

(271 citation statements)

References 45 publications

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“…Occupancy of the Src SH2 domain is thought to result in the activation of Src, suggesting a role for FAK upstream of Src. 24 We discovered that by mediating TFII-I tyrosine phosphorylation at Tyr248, Src is involved in CD147-induced TFII-I activation, and the consensus tyrosine phosphorylation site at residue 248 is required for TFII-I stimulation of the ERSE, which is consistent with previous findings. 27 Tumor progression may occur as the result of anti-apoptotic mechanisms combined with a general tolerance to suboptimal microenvironmental conditions as a result of the cytoprotective components of the UPR.…”

Section: Discussionsupporting

confidence: 91%

“…These results further confirm the conclusion that CD147 is a cancer biomarker. 24 While the expression of the ER-resident chaperone Bip was undetectable by immunohistochemistry in all 42 normal liver tissue samples (Table 1a), Bip was expressed in the majority of the 98 hepatoma tissues (83.7%; Table 1a). These results reveal that Bip is highly elevated in human HCC tissues compared with normal liver tissues (Z ¼ À 7.179, P ¼ 0.000), which suggested that the UPR is activated in human HCC tissues.…”

Section: Resultsmentioning

confidence: 96%

“…Bip overexpression promotes the formation of the Bip-caspase complex and blocks the cleavage of procaspase into its active form, which results in decreased apoptosis. 24 ADR and VP-16 are widely used as anti-cancer drugs, and they exert their effects by binding to topoisomerase II-DNA complexes, thereby preventing DNA religation after replication. 33 However, intrinsic and acquired chemoresistance remains an obstacle to the successful management of cancer.…”

Section: Discussionmentioning

confidence: 99%

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CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

Tang

Zhang

et al. 2012

Cell Death Differ

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The unfolded protein response (UPR) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. However, tumor-specific UPR transducers are largely unknown. In the present study, we identified CD147, a cancer biomarker, as an UPR inducer in hepatocellular carcinoma (HCC). The expression of the major UPR target, Bip, was found to be positively associated with CD147 in human hepatoma tissues. By phosphorylating FAK and Src, CD147-enhanced TFII-I tyrosine phosphorylation at Tyr248. CD147 also induced p-TFII-I nuclear localization and binding to the Bip promoter where endoplasmic reticulum (ER) stress response element 1 (ERSE1) ( À 82/ À 50) is the most efficient target of the three ERSEs, thus increasing transcription of Bip. Furthermore, by inducing UPR, CD147 inhibited HCC cell apoptosis and decreased cell Adriamycin chemosensitivity, thus decreasing the survival rate of hepatoma-bearing nude mice. Together, these results reveal pivotal roles for CD147 in modulating the UPR in HCC and raise the possibility that CD147 is a target that promotes HCC cell apoptosis and increases the sensitivity of tumors to anti-cancer drugs. Therefore, CD147 inhibition provides an opportunity to enhance the efficacy of existing agents and represents a novel target for HCC treatment. The uncontrolled growth and insufficient vascularization of a tumor mass lead to a stressed state in the tumor microenvironment, which includes low oxygen supply, nutrient deprivation and pH changes. Microenvironment stresses directly impinge on the luminal milieu of the endoplasmic reticulum (ER) and might be sufficiently severe to cause ER stress (ERS). 1 These ERS conditions activate a range of cellular stress response pathways, including the unfolded protein response (UPR). 2,3 UPR activation has profound consequences for tumor growth and resistance to radiotherapy and chemotherapy. [4][5][6] Therefore, the UPR might be responsible for the failure of some patients to respond to treatment and is associated with a poor prognosis. 7 Given the observation that UPR is correlated with certain types of aggressive tumors, drug resistance, recurrence and poor survival, 8-11 the inhibition of the UPR pathway may yield more efficient treatments for cancer.Although there is sufficient evidence to indicate that the UPR is generally activated in solid tumors, the UPR remains poorly characterized in cancers. The three major UPR transducers are inositol-requiring enzyme 1 (IRE1), pancreatic kinase-like ER kinase (PERK) and the UPR-specific transcription factor, activating transcription factor 6 (ATF6).These factors all sense the presence of unfolded proteins in the ER lumen and transduce signals to the nucleus that activate the transcription of UPR target genes, such as Bip (also called glucose-regulated protein 78). 12-14 The overexpression of Bip as a result of the three major transducers has been reported in malignant breast disease, colon cancer and gastric and esophageal adenocarcinomas. [15][16][17][18] It has also been...

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

Tang

Zhang

et al. 2012

Cell Death Differ

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“…For example, GRP78 can suppress EnR stress-induced apoptosis by sequestering caspase-7 and inhibiting its activation [84,85]. GRP78 can also inhibit proapoptotic protein BIK [86]. There may also be a contribution from growth factor receptor (GFR) signalling to GRP78 overexpression-induced resistance, since membrane-bound GRP78 can activate RAS-MAPK and PI3K -AKT pathways in other cells [87,88].…”

Section: Discussionmentioning

confidence: 99%

Modelling the effect of GRP78 on anti-oestrogen sensitivity and resistance in breast cancer

et al. 2013

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One contribution of 11 to a Theme Issue 'Integrated cancer biology models'. Understanding the origins of resistance to anti-oestrogen drugs is of critical importance to many breast cancer patients. Recent experiments show that knockdown of GRP78, a key gene in the unfolded protein response (UPR), can re-sensitize resistant cells to anti-oestrogens, and overexpression of GRP78 in sensitive cells can cause them to become resistant. These results appear to arise from the operation and interaction of three cellular systems: the UPR, autophagy and apoptosis. To determine whether our current mechanistic understanding of these systems is sufficient to explain the experimental results, we built a mathematical model of the three systems and their interactions. We show that the model is capable of reproducing previously published experimental results and some new data gathered specifically for this paper. The model provides us with a tool to better understand the interactions that bring about anti-oestrogen resistance and the effects of GRP78 on both sensitive and resistant breast cancer cells.

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“…The plasmid pcDNA3/His-Grp78 has been previously described. 38 Antibody against LC3 was either a gift from Dr. R Kopito (Stanford University, Stanford, CA) or purchased from MBL International. Antibodies used for western blot analysis include Beclin1 (goat polyclonal IgG for immunoprecipitation, Santa Cruz Biotechnology; mouse monoclonal IgG for blotting, BD Pharmingen), phospho-JNK1 (mouse monoclonal IgG, Promega), PI3KC3 (rabbit polyclonal IgG, Invitrogen), b-actin (AC15, mouse IgG, Sigma); CHOP (B3, mouse IgG1), ATF4 (rabbit polyclonal), JNK1 (rabbit polyclonal IgG) and XBP-1 (rabbit polyclonal) from Santa Cruz Biotechnology; phospho-eIF2a (rabbit polyclonal IgG) and eIF2a (rabbit polyclonal IgG) from Cell Signaling Biotechnology; GRP78 (mouse monoclonal IgG) from BD Pharmingen; GRP78 (rabbit polyclonal antiserum), GRP94 (rat monoclonal IgG) and KDEL (mouse monoclonal IgG) from Stressgen.…”

Section: Methodsmentioning

confidence: 99%

The unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells

et al. 2008

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In mammalian cells, endoplasmic reticulum (ER) stress has recently been shown to induce autophagy and the induction requires the unfolded protein response (UPR) signaling pathways. However, little is known whether autophagy regulates UPR pathways and how specific UPR targets might control autophagy. Here, we demonstrated that although ER stress-induced autophagy was suppressed by class III phosphatidylinositol-3 0 -kinase (PI3KC3) inhibitor 3-methyladenine (3-MA), wortmannin and knockdown of Beclin1 using small interfering RNA (siRNA), only 3-MA suppressed UPR activation. We discovered that the UPR regulator and ER chaperone GRP78/BiP is required for stress-induced autophagy. In cells in which GRP78 expression was knocked down by siRNA, despite spontaneous activation of UPR pathways and LC3 conversion, autophagosome formation induced by ER stress as well as by nutrition starvation was inhibited. GRP78 knockdown did not disrupt PI3KC3-Beclin1 association. However, electron microscopic analysis of the intracellular organelle structure reveals that the ER, a putative membrane source for generating autophagosomal double membrane, was massively expanded and disorganized in cells in which GRP78 was knocked down. ER expansion is known to be dependent on the UPR transcription factor XBP-1. Simultaneous knockdown of GRP78 and XBP-1 recovered normal levels of stress-induced autophagosome formation. Thus, these studies uncover 3-MA as an inhibitor of UPR activation and establish GRP78 as a novel obligatory component of autophagy in mammalian cells.

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GRP78/BiP Inhibits Endoplasmic Reticulum BIK and Protects Human Breast Cancer Cells against Estrogen Starvation–Induced Apoptosis

Cited by 282 publications

References 45 publications

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

Modelling the effect of GRP78 on anti-oestrogen sensitivity and resistance in breast cancer

The unfolded protein response regulator GRP78/BiP is required for endoplasmic reticulum integrity and stress-induced autophagy in mammalian cells

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