Function and mutual interaction of BiP-, PERK-, and IRE1α-dependent signalling pathways in vascular tumours.
Cell Movement
Cell Proliferation
Cells, Cultured
Endoplasmic Reticulum Chaperone BiP
Endoribonucleases
/ genetics
Endothelial Cells
/ enzymology
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Heat-Shock Proteins
/ genetics
Hemangioma
/ enzymology
Hemangiosarcoma
/ enzymology
Human Umbilical Vein Endothelial Cells
/ enzymology
Humans
Neovascularization, Pathologic
Protein Serine-Threonine Kinases
/ genetics
Signal Transduction
Vascular Endothelial Growth Factor Receptor-2
/ genetics
X-Box Binding Protein 1
/ genetics
eIF-2 Kinase
/ genetics
VEGFR2
angiosarcoma
chaperone
haemangioma
tumour angiogenesis
unfolded protein response, crosstalk
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
29
11
2019
revised:
19
02
2020
accepted:
09
03
2020
pubmed:
14
3
2020
medline:
22
9
2020
entrez:
14
3
2020
Statut:
ppublish
Résumé
Spontaneously regressing infantile haemangiomas and aggressive angiosarcomas are vascular tumours with excessive angiogenesis. When analysing haemangiomas and angiosarcomas immunohistochemically with respect to their chaperone profiles we found that angiosarcomas have significantly elevated protein levels of binding immunoglobulin protein (BIP) and PERK with concomitant attenuated IRE1α levels, whereas haemangioma tissue exhibits the same pattern as embryonal skin tissue. We show that BiP is essential for the maintenance of VEGFR2 protein, which is expressed in the endothelium of both tumour types. When studying the effects of BiP, the IRE1α/Xbp1 -, and PERK/ATF4-signalling pathways on the migration and tube-forming potential of endothelial cells, we show that downregulation of BiP, as well as inhibition of the kinase activity of IRE1α, inhibit in vitro angiogenesis. Downregulation of PERK (PKR-like kinase; PKR = protein kinase R) levels promotes Xbp1 splicing in endoplasmic reticulum (ER)-stressed cells, indicating that in angiosarcoma the elevated PERK levels might result in high levels of unspliced Xbp1, which have been reported to promote cell proliferation and increase tumour malignancy. The data presented in this study revealed that in addition to BiP or PERK, the kinase domains of IRE1α and Xbp1 could be potential targets for the development of novel therapeutic approaches for treating angiosarcomas and to control tumour angiogenesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Substances chimiques
Endoplasmic Reticulum Chaperone BiP
0
Heat-Shock Proteins
0
X-Box Binding Protein 1
0
XBP1 protein, human
0
KDR protein, human
EC 2.7.10.1
Vascular Endothelial Growth Factor Receptor-2
EC 2.7.10.1
EIF2AK3 protein, human
EC 2.7.11.1
ERN1 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
eIF-2 Kinase
EC 2.7.11.1
Endoribonucleases
EC 3.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
123-134Informations de copyright
© 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Références
Ravi V, Patel S. Vascular sarcomas. Curr Oncol Rep 2013; 15: 347-355.
Jinnin M, Ishihara T, Boye E, et al. Recent progress in studies of infantile hemangioma. J Dermatol 2010; 37: 939-955.
Lahat G, Dhuka AR, Hallevi H, et al. Angiosarcoma: clinical and molecular insights. Ann Surg 2010; 251: 1098-1106.
Itakura E, Yamamoto H, Oda Y, et al. Detection and characterization of vascular endothelial growth factors and their receptors in a series of angiosarcomas. J Surg Oncol 2008; 97: 74-81.
Arbiser JL, Bonner MY, Berrios RL. Hemangiomas, angiosarcomas, and vascular malformations represent the signaling abnormalities of pathogenic angiogenesis. Curr Mol Med 2009; 9: 929-934.
Arbiser JL, Larsson H, Claesson-Welsh L, et al. Overexpression of VEGF 121 in immortalized endothelial cells causes conversion to slowly growing angiosarcoma and high level expression of the VEGF receptors VEGFR-1 and VEGFR-2 in vivo. Am J Pathol 2000; 156: 1469-1476.
Jinnin M, Medici D, Park L, et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med 2008; 14: 1236-1246.
Yonemori K, Tsuta K, Ando M, et al. Contrasting prognostic implications of platelet-derived growth factor receptor-beta and vascular endothelial growth factor receptor-2 in patients with angiosarcoma. Ann Surg Oncol 2011; 18: 2841-2850.
Antonescu CR, Yoshida A, Guo T, et al. KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors. Cancer Res 2009; 69: 7175-7179.
Wang Y, Alam GN, Ning Y, et al. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway. Cancer Res 2012; 72: 5396-5406.
Tsaryk R, Bartholoma NM, Simiantonaki N, et al. Endoplasmic reticulum-resident chaperones modulate the inflammatory and angiogenic responses of endothelial cells. Br J Dermatol 2015; 173: 416-427.
Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011; 334: 1081-1086.
DuRose JB, Scheuner D, Kaufman RJ, et al. Phosphorylation of eukaryotic translation initiation factor 2alpha coordinates rRNA transcription and translation inhibition during endoplasmic reticulum stress. Mol Cell Biol 2009; 29: 4295-4307.
Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8: 519-529.
Ma Y, Hendershot LM. Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress. J Biol Chem 2003; 278: 34864-34873.
Zeng L, Xiao Q, Chen M, et al. Vascular endothelial cell growth-activated XBP1 splicing in endothelial cells is crucial for angiogenesis. Circulation 2013; 127: 1712-1722.
Ghosh R, Lipson KL, Sargent KE, et al. Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS One 2010; 5: e9575.
Jaffe EA, Nachman RL, Becker CG, et al. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 1973; 52: 2745-2756.
Peters K, Schmidt H, Unger RE, et al. Software-supported image quantification of angiogenesis in an in vitro culture system: application to studies of biocompatibility. Biomaterials 2002; 23: 3413-3419.
Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 1987; 8: 138-140.
Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med 2012; 2: a006502.
Jayasinghe C, Simiantonaki N, Habedank S, et al. The relevance of cell type- and tumor zone-specific VEGFR-2 activation in locally advanced colon cancer. J Exp Clin Cancer Res 2015; 34: 42.
Yoo SA, You S, Yoon HJ, et al. A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis. J Exp Med 2012; 209: 871-886.
Paton AW, Beddoe T, Thorpe CM, et al. AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. Nature 2006; 443: 548-552.
Mulliken JB, Zetter BR, Folkman J. In vitro characteristics of endothelium from hemangiomas and vascular malformations. Surgery 1982; 92: 348-353.
Dong D, Ni M, Li J, et al. Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res 2008; 68: 498-505.
Dong D, Stapleton C, Luo B, et al. A critical role for GRP78/BiP in the tumor microenvironment for neovascularization during tumor growth and metastasis. Cancer Res 2011; 71: 2848-2857.
Li Z, Zhang L, Zhao Y, et al. Cell-surface GRP78 facilitates colorectal cancer cell migration and invasion. Int J Biochem Cell Biol 2013; 45: 987-994.
Zhang J, Jiang Y, Jia Z, et al. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin Exp Metastasis 2006; 23: 401-410.
Atkins C, Liu Q, Minthorn E, et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res 2013; 73: 1993-2002.
Blais JD, Addison CL, Edge R, et al. Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress. Mol Cell Biol 2006; 26: 9517-9532.
Bu Y, Diehl JA. PERK integrates oncogenic signaling and cell survival during cancer development. J Cell Physiol 2016; 231: 2088-2096.
Lin JH, Li H, Yasumura D, et al. IRE1 signaling affects cell fate during the unfolded protein response. Science 2007; 318: 944-949.
Katanasaka Y, Ishii T, Asai T, et al. Cancer antineovascular therapy with liposome drug delivery systems targeted to BiP/GRP78. Int J Cancer 2010; 127: 2685-2698.
Ren P, Chen C, Yue J, et al. High expression of glucose-regulated protein 78 (GRP78) is associated with metastasis and poor prognosis in patients with esophageal squamous cell carcinoma. Onco Targets Ther 2017; 10: 617-625.
Pyrko P, Schonthal AH, Hofman FM, et al. The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res 2007; 67: 9809-9816.
Fu Y, Wey S, Wang M, et al. Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium. Proc Natl Acad Sci U S A 2008; 105: 19444-19449.
Wey S, Luo B, Tseng CC, et al. Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling. Blood 2012; 119: 817-825.
Martin S, Lamb HK, Brady C, et al. Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78. Br J Cancer 2013; 109: 433-443.
Luo S, Mao C, Lee B, et al. GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development. Mol Cell Biol 2006; 26: 5688-5697.
Wang M, Ye R, Barron E, et al. Essential role of the unfolded protein response regulator GRP78/BiP in protection from neuronal apoptosis. Cell Death Differ 2010; 17: 488-498.
Takahashi T, Shibuya M. The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts. Oncogene 1997; 14: 2079-2089.
Lee J Jr, Chen CH, Chen YH, et al. COSMC is overexpressed in proliferating infantile hemangioma and enhances endothelial cell growth via VEGFR2. PLoS One 2013; 8: e56211.
Rahimi N, Costello CE. Emerging roles of post-translational modifications in signal transduction and angiogenesis. Proteomics 2015; 15: 300-309.
Bai X, Cerimele F, Ushio-Fukai M, et al. Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. J Biol Chem 2003; 278: 35501-35507.
Byrd AE, Aragon IV, Brewer JW. MicroRNA-30c-2* limits expression of proadaptive factor XBP1 in the unfolded protein response. J Cell Biol 2012; 196: 689-698.
Nekrutenko A, He J. Functionality of unspliced XBP1 is required to explain evolution of overlapping reading frames. Trends Genet 2006; 22: 645-648.
Guo F, Lin EA, Liu P, et al. XBP1U inhibits the XBP1S-mediated upregulation of the iNOS gene expression in mammalian ER stress response. Cell Signal 2010; 22: 1818-1828.
Huang C, Wu S, Ji H, et al. Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library. Sci Adv 2017; 3: e1701383.
Nagelkerke A, Bussink J, Mujcic H, et al. Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response. Breast Cancer Res 2013; 15: R2.
Feng YX, Sokol ES, Del Vecchio CA, et al. Epithelial-to-mesenchymal transition activates PERK-eIF2alpha and sensitizes cells to endoplasmic reticulum stress. Cancer Discov 2014; 4: 702-715.
Vassileva G, Chen SC, Zeng M, et al. Expression of a novel murine type I IFN in the pancreatic islets induces diabetes in mice. J Immunol 2003; 170: 5748-5755.
Gao Y, Sartori DJ, Li C, et al. PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis. Mol Cell Biol 2012; 32: 5129-5139.
Romero-Ramirez L, Cao H, Nelson D, et al. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res 2004; 64: 5943-5947.
Romero-Ramirez L, Cao H, Regalado MP, et al. X box-binding protein 1 regulates angiogenesis in human pancreatic adenocarcinomas. Transl Oncol 2009; 2: 31-38.
Maly DJ, Papa FR. Druggable sensors of the unfolded protein response. Nat Chem Biol 2014; 10: 892-901.