Low-Density Lipoprotein Receptor-Related Protein 8 at the Crossroad between Cancer and Neurodegeneration
Abstract
:1. Introduction
2. LDLR Family
2.1. LDLR
2.2. LRP1
2.3. LRP2/Megalin
2.4. VLDLR
2.5. LRP4
2.6. LR11/SorLA
2.7. LRP5/6
2.8. LRP1B
LDLR Family Members | CNS Roles/ Neurodegeneration | Molecular Pathway | Refs. | Cancer Related Roles | Molecular Pathway | Refs. |
---|---|---|---|---|---|---|
LDLR | Modulation of amyloid clearance and/or deposition | ApoE interaction | [25,27,28] | Downregulation of cell proliferation and metastasis | Downregulation of LDLR through MEK/ERK stimulation | [29] |
LRP1 | Neuronal survival | ApoE-dependent activation of PKCδ and inactivation of GSK3β | [35] | |||
APP trafficking regulation and processing and Aβ clearance | LRP1 antagonist RAP increases cell surface levels of APP and significantly reduce Aβ synthesis. In the absence of LRP1, Aβ production, APP secretion, APP internalization, turnover of full-length APP and stability of APP C-terminal fragments are affected. At the site of the BBB, surface LRP1-mediated extrusion of cerebral Aβ into the luminal side Soluble LRP1 in the periphery sequesters free Aβ in circulation. | [36,37,38,39] | Cellular migration and invasion | Expression of MMP-2 and MMP-9 through ERK in human glioblastoma Serpin PN-1-dependend MMP-9 expression through ERK activation in breast cancer | [43,44] | |
Calcium-related cellular processes | ApoE4, but not ApoE3, significantly increased the resting calcium, the calcium response to NMDA-R and the neurotoxicity. | [34] | Cell proliferation, tumor invasion and angiogenesis | LRP1 expression has been linked to neoplastic aggressiveness due to high histological grade and elevated mitotic index. Regeneration of the uPAR receptor system | [45] | |
Neurite outgrowth, synaptic plasticity, learning and memory modulation | Upon TTR binding to LRP2, Src, NMDA-Rs, ERK1/2, CREB and Akt activation and/or a pathway involving RIP and the formation of LRP2-ICD MT-IIA binding to LRP2 stimulates neurite outgrowth via signal transduction pathways activated by the NPxY motifs of LRP2. | [49,52] | Cell survival and proliferation | LRP2 is frequently expressed in malignant melanoma. Modulation of phosphorylated Akt and ERK levels | [7] | |
VLDLR | Regulation of the migration and layering of the neurons in the cortex and the cerebellum | Reelin-induced Dab1 binding to VLDLR activates SFK and Abl families, together with LRP8. Pafah1b complex mediates downstream effects of VLDLR on neuronal migration. | [59,60,119] | Cell proliferation, migration and metastasis | VLDLR II is overexpressed in lymph node and distant metastasis in gastric and breast cancer patients, promoting cell proliferation and migration. ATRA attenuates proliferation and migration through significant decreases in VLDLR II, while PMA has the opposite effect on VLDLR II, which activates β-catenin/TCF signaling and modulation of MMP-2 and MMP-9. | [8,61] |
LRP4 | Synaptic homeostasis | LRP4 mutant astrocytes suppressed glutamatergic transmission by enhancing the release of ATP. | [63] | |||
Synaptic transmission, LTP and cognitive function | LRP4 KO shows deficits in cognitive tasks with aberrant synapse form and function and loss of LTP. | [65] | EMT promotion | LRP4 is overexpressed in papillary thyroid and gastric cancers, where it promotes EMT through PI3K/AKT pathway and modulation of N-cadherin, ZEB1 and EZH2. | [70,71] | |
Adult hippocampal neurogenesis | LRP4 mutation blocks NPSC proliferation. Agrin-LRP4-Ror2 signaling is involved in NSPC proliferation. | [66] | Cell proliferation, migration and invasion | LRP8 downregulation affects colony formation and migratory and invasive capacities through PI3K/AKT pathway. miR-140-5p negatively regulates LRP4. | [70,71] | |
Formation and maintenance of the neuromuscular junction | Agrin–LRP4 interaction via MuSK, Dok7 and rapsyn mediates AChR clustering. | [67,68] | ||||
LR11/ SorLA | Regulation of APP processing and Aβ levels | Interaction with APP, enhancement of APP in endosomal compartments and Golgi, modulation of APP processing and reduction of Aβ levels | [72,73] | Cell proliferation | Regulation of endosomal trafficking and oncogenic fitness of HER2, promoting PI3K-dependent HER2 signaling | [78] |
LRP6 | Synaptic function and integrity |
Activation of Wnt signaling | [104] | Cell proliferation, survival and differentiation, tumor growth | Co-receptor for WNT and Wnt activator | [98,103] |
LRP1B | Regulation of APP endocytic rate and Aβ levels reduction | Interaction with APP | [118] | Suppression of cell growth, invasion, migration, colony and tumor formation | Reduction of matrix metalloproteinase 2 level and negative regulation of uPAR DNA methylation | [106,107,108] |
3. Apolipoprotein E Receptor 2 (LRP8)
3.1. LRP8 and Cancer
3.2. LRP8 in Neurodegeneration
4. Final Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cancer Types | LRP8 Cancer Roles | Main Findings & Molecular Mechanism | In Vitro E in Vivo Models | Refs. |
---|---|---|---|---|
Osteosarcoma | Cell proliferation and anti-apoptotic effect | LRP8 is overexpressed in osteosarcoma tissues. LRP8 enhances PD-L1 expression via STAT3, evading the host immune system. | Cell lines: MG63 and U2OS | [141] |
TNBC TNBC | Cell proliferation, anti-apoptotic effect and colony formation | LRP8 is overexpressed in TNBC patients. LRP8 depletion induces arrest of the cell cycle and apoptosis. LRP8 knockdown impairs colony formation. | Cell lines: BT-474, T47D, MCF7, ZR-75-1, SKBR3, HCC1569, HCC1954, BT-20, HCC1143, HCC38, HCC70, MDA-MB-468 and MDA-MB-45 In vivo model: xenograft mice model (MDA-MB-468) | [142] |
Tumorigenesis and chemoresistance | LRP8 silencing suppresses BCSCs and tumorigenesis in TNBC via Wnt signaling inhibition. LRP8 KO shifts TNBC cells to a more differentiated phenotype, sensitizing them to chemotherapy. | Cell lines: HCC1937 and SUM149 In vivo model: xenograft NOD/SCID mice (SUM149) | [9] | |
Gastric cancer | Cell migration | Mycophenolic acid downregulates LRP8, reducing cell migration. | Cell lines: AGS and Hs746T | [143] |
Cancer progression | MiR-142 suppresses progression of gastric carcinoma via directly targeting LRP8. | Cell lines: AGS, MKN-45, MKN-28, SGC-7901 and BGC-823 | [144] | |
Hepatocellular carcinoma | Pharmacoresistance | LRP8-dependent activation of β-catenin pathway suppresses Sorafenib induced apoptosis. | Cell lines: Huh7 and MHCC-97H | [145] |
Melanoma | Suppression of cell invasion and endothelial recruitment | miR-1908, miR-199a-5p, and miR-199a-3p limit ApoE secretion suppressing LRP8 endothelial engagement | Cell lines: TWM-266-4, A375, SK-Mel-28, HT-144, A2058, MeWo, SK-Mel-2, SK-Mel-28, A375, WM-266-4, HT-144, and A2058 In vivo model: xenograft NOD scid mice (MeWo) | [146] |
Lung cancer | Cancer progression and cisplatin resistance | miR-30b-5p inhibits lung cancer cell viability, migration and invasion and enhances cell sensitivity to DDP via targeting LRP8. | Cell lines: A549, A549/DDP, NCI-H1299, NCIH446 and H1650 In vivo model: xenograft BALB/c nude mice | [147] |
Cell proliferation, migration, invasion, EMT, tumor growth (NSCLC) | LRP8 is markedly overexpressed in NSCLC patients with poor clinicopathological characteristics and prognosis. LRP8 KO elicits tumor-suppressive functions by suppressing the Wnt/β-catenin pathway. | Cell lines: 95-D, H1299, H460, HCC-827, A549, PC-9, and H1975 | [148] | |
Prostate cancer | Cancer progression | miR-455-5p inhibits cancer cell migration and invasive abilities through LRP8 downregulation. | Cell lines: PC3, DU145, and C4-2 | [149] |
Pancreatic cancer | Cell proliferation | ApoE2-LRP8 induces phosphorylation of ERK1/2 to activate c-Myc, promoting cyclin D1, cdc2 and cyclin B1 expression and reducing p21Waf1 activity. | Cell lines: MIA PaCa-2, Capan-2, PANC-1, Bxpc-3 | [150] |
LRP8 Interactors | Roles in CNS and Neurodegeneration | LRP8 Main Findings & Molecular Mechanism Related to CNS | In Vitro E in Vivo Models | Refs. |
---|---|---|---|---|
ApoE | Neurodegeneration | Increase in APP endocytosis and Aβ production via X11α or X11β (X11α/β) | Neuroblastoma N2a cells | [157] |
Reelin | Synaptic plasticity | Activation of synaptic plasticity genes mediated by the activation of neuronal enhancers | Primary cortical neurons/heterozygous Reeler and LRP8-KO mice | [124] |
Enhancement of LRP8 proteolytic processing, followed by LRP8-ICD induced transcription | ||||
Modulation of NMDA-R phosphorylation via SFKs and Dab1 followed by increased Calcium influx | Primary wild-type cortical neurons/Dab1 knock-out neurons | [163] | ||
Control of neuronal migration and cellular layer formation in the developing brain | Partial inversion of the neuronal layers in the neocortex | VLDL and LRP8 KO mice | [59] | |
Neurodegeneration | Activation of the signaling pathway involving Dab1-PI3K-AKT leading to the inhibition of GSK3β and in turn phosphorylation of tau | Primary neurons | [161] | |
Trombospondin-1 (THBS-1) | Postnatal neuronal migration | Promotion of neuroblast chain migration | SVZ explants from wild-type mice, ApoER2−/− VLDLR−/− mice and THBS-1−/− mice on a C57BL6/J background | [193] |
Clusterin | Postnatal neuronal migration | Modulation of a cell proliferative signal in migrating neuronal precursors via Dab1-PI3K/Akt signal | SVZ explants from wild-type mice | [194] |
Selenoprotein P (Sepp1) | Preservation of neurological function and survival | Selenium transport | Sepp1−/− and Sepp1+/+ male mice ApoER2−/− mice (strain name, B6;129S6-Lrp8tm1Her/J) | [199] |
F-Spondin | Neurodegeneration | LRP8 cleavage increase and Aβ production decrease | COS7 and HEK293 cells transfected with reelin, spondin, thrombospondin or F-spondin | [158] |
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Passarella, D.; Ciampi, S.; Di Liberto, V.; Zuccarini, M.; Ronci, M.; Medoro, A.; Foderà, E.; Frinchi, M.; Mignogna, D.; Russo, C.; et al. Low-Density Lipoprotein Receptor-Related Protein 8 at the Crossroad between Cancer and Neurodegeneration. Int. J. Mol. Sci. 2022, 23, 8921. https://doi.org/10.3390/ijms23168921
Passarella D, Ciampi S, Di Liberto V, Zuccarini M, Ronci M, Medoro A, Foderà E, Frinchi M, Mignogna D, Russo C, et al. Low-Density Lipoprotein Receptor-Related Protein 8 at the Crossroad between Cancer and Neurodegeneration. International Journal of Molecular Sciences. 2022; 23(16):8921. https://doi.org/10.3390/ijms23168921
Chicago/Turabian StylePassarella, Daniela, Silvia Ciampi, Valentina Di Liberto, Mariachiara Zuccarini, Maurizio Ronci, Alessandro Medoro, Emanuele Foderà, Monica Frinchi, Donatella Mignogna, Claudio Russo, and et al. 2022. "Low-Density Lipoprotein Receptor-Related Protein 8 at the Crossroad between Cancer and Neurodegeneration" International Journal of Molecular Sciences 23, no. 16: 8921. https://doi.org/10.3390/ijms23168921