GRP78 confers the resistance to 5-FU by activating the c-Src/LSF/TS Axis in hepatocellular carcinoma

Gu, Yue; Li, Hongdan; Zhao, Liang; Zhao, Song; He, Wu; Li, Rui; Su, Chang; Zheng, Haixue; Su, Rongjian

doi:10.18632/oncotarget.5603

Cited by 22 publications

(17 citation statements)

References 34 publications

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“…However, when tyrosine 269 (Y269) of the PSY motif was replaced with an alanine (A), the YAP-TFCP2 interaction disappeared (Figures 3D and S3E). Unlike the nuclear localization of WT-YAP and WT-TFCP2 in liver cancer cells, both YAP-Del-2WW (deletion of both two WW domains) and TFCP2-Y269A were excluded from the nucleus ( Figure S3F), where YAP and TFCP2 function (Gu et al, 2015;Guo et al, 2016). Moreover, both YAP-Del-2WW and TFCP2-Y269A failed to form the red signal representing the direct interaction between YAP and TFCP2, as measured by the PLA experiment ( Figure S3G).…”

Section: Tfcp2 Is Required For Yap-induced Malignancymentioning

confidence: 98%

TFCP2 Is Required for YAP-Dependent Transcription to Stimulate Liver Malignancy

et al. 2017

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Although YAP-dependent transcription is closely associated with liver tumorigenesis, the mechanism by which YAP maintains its function is poorly understood. Here, we show that TFCP2 is required for YAP-dependent transcription and liver malignancy. Mechanistically, YAP function is stimulated by TFCP2 via a WW-PSY interaction. TFCP2 also maintains YAP stability by inhibiting βTrCP. Notably, genomic co-occupancy of YAP and TFCP2 is revealed. TFCP2 acts as a transcription co-factor that stimulates YAP transcription by facilitating YAP binding with YAP binding motif (YBF)-containing transcription factors. Interestingly, TFCP2 also stimulated the YAP-TEAD interaction and TEAD target gene expression. Finally, several genes co-regulated by YAP and TFCP2 that contribute to YAP-dependent tumorigenesis are identified and verified. Thus, we establish a model showing that TFCP2 acts as a YAP co-factor to maintain YAP-dependent transcription in liver cancer cells, suggesting that simultaneous targeting of both YAP and TFCP2 may be an effective therapeutic approach.

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Section: Tfcp2 Is Required For Yap-induced Malignancymentioning

confidence: 98%

TFCP2 Is Required for YAP-Dependent Transcription to Stimulate Liver Malignancy

et al. 2017

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“…Lung and ovarian cancer, osteosarcoma Induction of chemoresistance to cisplatin and 5-FU [105][106][107][108] Ovarian cancer Enhancement of drug sensitivity to cisplatin by increasing mitochondrial cytochrome c release via inhibition of Mortalin [109] Colorectal and ovarian cancer Acquirement of 5-FU resistance via regulation of PI3K/AKT/mTOR and c-Src/LSF/TS signal by GRP78 [108,110] Cervical cancer Induction of apoptosis by regulating mitochondrial related proteins via GRP78 knockdown [111] Osteosarcoma Decrease of HSP70 expression by miR-223, deactivation of JNK/JUN signal, and enhancement of cisplatin sensitivity [106] Non-small cell lung cancer Promotion of cellular resistance to EGFR tyrosine inhibitors by enhancing gene mutation and tumor heterogeneity via inhibition of HSP70 [112] HSP90 Osteosarcoma Induction of chemoresistance by inducing autophagy via PI3K/AKT/mTOR pathway and inhibiting of apoptosis via JNK/p38 pathway [113] Colon cancer Acquirement of drug resistance by activating HSP90 client proteins, such as EGFR, IGF-IR, and Src [114] Ovarian cancer Regulation of various drug resistant genes, such as LRP, GST-π, p53, bcl-2, survivin, ERCC1, XRCC1, BRCA1 and BRCA2 [115] Pancreatic cancer Induction of drug resistance to 5-FU and gemcitabine by regulating AKT and MAPK and enhancing apoptosis via inhibition of HSP90 [116] Breast and gastric cancer AUY-022 (HSP90 inhibitor), increased effects of lapatinib via inhibition of HER2 and AKT pathway [117] HSP27 is associated with chemoresistance and poor prognosis in multiple cancers, including gastric, liver, prostate, lung, and colorectal cancers [16]. HSP27 enhances multidrug-resistance in squamous cell carcinoma of tongue (SCCT) through hyperactivation of NF-κB.…”

Section: Hsp40mentioning

confidence: 99%

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

Yun

Kim

Lim

et al. 2019

Cells

204

158

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Heat shock proteins (HSPs) constitute a large family of molecular chaperones classified by their molecular weights, and they include HSP27, HSP40, HSP60, HSP70, and HSP90. HSPs function in diverse physiological and protective processes to assist in maintaining cellular homeostasis. In particular, HSPs participate in protein folding and maturation processes under diverse stressors such as heat shock, hypoxia, and degradation. Notably, HSPs also play essential roles across cancers as they are implicated in a variety of cancer-related activities such as cell proliferation, metastasis, and anti-cancer drug resistance. In this review, we comprehensively discuss the functions of HSPs in association with cancer initiation, progression, and metastasis and anti-cancer therapy resistance. Moreover, the potential utilization of HSPs to enhance the effects of chemo-, radio-, and immunotherapy is explored. Taken together, HSPs have multiple clinical usages as biomarkers for cancer diagnosis and prognosis as well as the potential therapeutic targets for anti-cancer treatment.

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“…The binding of GRP78 to most of these ligands activates the AKT/PI3K pro-survival pathway (Misra et al, 2004, 2006; Philippova et al, 2008; Figure 1). Soluble Cripto has also been shown to bind cell-surface GRP78/BiP initiating PI3K and MAPK signaling via Src activation (Gray and Vale, 2012) or binding directly to c-Src (Gu et al, 2015). Indeed, cell-surface GRP78 is also involved in cell-matrix adhesion by α1-integrin interaction and focal adhesion kinase (FAK) regulation.…”

Section: Grp78 a Very Important Protein With Multiple Functions In Mmentioning

confidence: 99%

GRP78 at the Centre of the Stage in Cancer and Neuroprotection

2017

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The 78-kDa glucose-regulated protein GRP78, also known as BiP and HSP5a, is a multifunctional protein with activities far beyond its well-known role in the unfolded protein response (UPR) which is activated after endoplasmic reticulum (ER) stress in the cells. Most of these newly discovered activities depend on its position within the cell. GRP78 is located mainly in the ER, but it has also been observed in the cytoplasm, the mitochondria, the nucleus, the plasma membrane, and secreted, although it is dedicated mostly to engage endogenous cytoprotective processes. Hence, GRP78 may control either UPR and macroautophagy or may activated phosphatidylinositol 3-kinase (PI3K)/AKT pro-survival pathways. GRP78 influences how tumor cells survive, proliferate, and develop chemoresistance. In neurodegeneration, endogenous mechanisms of neuroprotection are frequently insufficient or dysregulated. Lessons from tumor biology may give us clues about how boosting endogenous neuroprotective mechanisms in age-related neurodegeneration. Herein, the functions of GRP78 are revealed at the center of the stage of apparently opposite sites of the same coin regarding cytoprotection: neurodegeneration and cancer. The goal is to give a comprehensive and critical review that may serve to guide future experiments to identify interventions that will enhance neuroprotection.

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GRP78 confers the resistance to 5-FU by activating the c-Src/LSF/TS Axis in hepatocellular carcinoma

Cited by 22 publications

References 34 publications

TFCP2 Is Required for YAP-Dependent Transcription to Stimulate Liver Malignancy

TFCP2 Is Required for YAP-Dependent Transcription to Stimulate Liver Malignancy

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

GRP78 at the Centre of the Stage in Cancer and Neuroprotection

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