Therapeutic Targeting of Low-density lipoprotein receptor-related protein-1 (LRP1) gene in Ovarian Cancer: A Comprehensive Review

R.B. Devi Krishna; Nandini Krishnamurthy; Sanjana Murali; Preet Agarwal; Elizabeth Rani Chellappan; Leena Dennis  Joseph; Banu Keerthana; Andrea Mary Francis

doi:10.20883/medical.e1221

Authors

R.B. Devi Krishna Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India https://orcid.org/0009-0000-3466-9800
Nandini Krishnamurthy Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India https://orcid.org/0009-0000-2710-3577
Sanjana Murali Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India https://orcid.org/0009-0006-3549-0080
Preet Agarwal Department of Gynaecology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India https://orcid.org/0000-0001-9907-5747
Elizabeth Rani Chellappan Department of Biotechnology, Hindustan College of Arts & Science, Chennai, Tamil Nadu, India https://orcid.org/0009-0000-6664-363X
Leena Dennis Joseph Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India https://orcid.org/0000-0002-9395-2961
Banu Keerthana Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India https://orcid.org/0000-0001-7858-8666
Andrea Mary Francis Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India https://orcid.org/0000-0003-2260-7199

DOI:

https://doi.org/10.20883/medical.e1221

Keywords:

ovarian cancer, proliferation, tumour, therapeutic target, clinical implication, LRP1

Abstract

Low-density lipoprotein receptor-related protein 1 (LRP1, also known as CD91) is a multifunctional endocytic and cell-signalling receptor widely expressed in various cell types, including neurons, fibroblasts, hepatocytes, muscle cells, astrocytes, and tumour cells. It maintains cellular homeostasis by mediating interactions with extracellular matrix proteins, growth factors, and proteases. These interactions enable LRP1 to act as a co-receptor that modulates and influences signalling pathways associated with cell migration, survival, and proliferation. In ovarian cancer, LRP1 is frequently activated and contributes to tumour progression. Functional studies have demonstrated that LRP1 promotes these malignant traits through activation of PI3K/Akt and MAPK/ERK pathways, while its inhibition suppresses proliferation and invasion. This review aims to comprehensively examine the functional role of LRP1 in ovarian cancer, with particular emphasis on its capacity to regulate tumour cell migration and invasion through key molecular pathways. Understanding these mechanisms may provide insights into novel therapeutic strategies for ovarian cancer treatment.

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References

Moch H. Female genital tumours: WHO Classification of Tumours, Volume 4. WHO classification of tumours. 2020.

Committee on the State of the Science in Ovarian Cancer Research; Board on Health Care Services; Institute of Medicine; National Academies of Sciences, Engineering, and Medicine. Ovarian Cancers: Evolving Paradigms in Research and Care. Washington (DC): National Academies Press (US); 2016 Apr 25.

Zhou W, Ma J, Zhao H, Wang Q, Guo X, Chen L, Cao Z, Xu J, Zhang B, Zhou X. Serum exosomes from epithelial ovarian cancer patients contain LRP1, which promotes the migration of epithelial ovarian cancer cells. Mol. Cell. Proteom. 2023 Apr 1;22(4):100520. https://doi.org/10.1016/j.mcpro.2023.100520.

International Agency for Research on Cancer. Global Cancer Observatory: Cancer Today. Lyon, France: IARC. Retrieved from GLOBOCAN 2022.

Bian W, Tang M, Jiang H, Xu W, Hao W, Sui Y, Hou Y, Nie L, Zhang H, Wang C, Li N. Low-density-lipoprotein-receptor-related protein 1 mediates Notch pathway activation. Dev. Cell. 2021 Oct 25;56(20):2902-19. https://doi.org/10.1016/j.devcel.2021.09.015.

Ortiz M, Wabel E, Mitchell K, Horibata S. Mechanisms of chemotherapy resistance in ovarian cancer. Cancer Drug Resist. 2022 Apr 3;5(2):304. https://doi.org/10.20517/cdr.2021.147.

Wang L, Wang X, Zhu X, Zhong L, Jiang Q, Wang Y, Tang Q, Li Q, Zhang C, Wang H, Zou D. Drug resistance in ovarian cancer: from mechanism to clinical trial. Mol. Cancer. 2024 Mar 28;23(1):66. https://doi.org/10.1186/s12943-024-01967-3.

Guo X, Yang F, Liu T, Chen A, Liu D, Pu J, Jia C, Wu Y, Yuan J, Ouyang N, Herz J. Loss of LRP1 Promotes Hepatocellular Carcinoma Progression via UFL1-Mediated Activation of NF-κB Signaling. Adv. Sci. 2024 Dec;11(45):2401672. https://doi.org/10.1002/advs.202401672.

Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. J. Clin. Invest. 2001 Sep 15;108(6):779-84. https://doi.org/10.1172/JCI13992.

Vormittag R, Bencur P, Ay C, Tengler T, Vukovich T, Quehenberger P, Mannhalter C, Pabinger I. Low-density lipoprotein receptor-related protein 1 polymorphism 663 C> T affects clotting factor VIII activity and increases the risk of venous thromboembolism. J. Thromb. Haemost. 2007 Mar;5(3):497-502. https://doi.org/10.1111/j.1538-7836.2007.02337.x.

Vitols S, Peterson C, Larsson O, Holm P, Åberg B. Elevated uptake of low density lipoproteins by human lung cancer tissue in vivo. Cancer Res. 1992 Nov 15;52(22):6244-6247.

Herz J, Hamann U, Rogne S, Myklebost O, Gausepohl H, Stanley KK. Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor. EMBO J. 1988 Dec 20;7(13):4119-27. https://doi.org/10.1002/j.1460-2075.1988.tb03306.x.

Kang HS, Kim J, Lee HJ, Kwon BM, Lee DK, Hong SH. LRP1-dependent pepsin clearance induced by 2′-hydroxycinnamaldehyde attenuates breast cancer cell invasion. Int. J. Biochem. Cell Biol. 2014 Aug 1;53:15-23. https://doi.org/10.1016/j.biocel.2014.04.021.

Coleman RL, Monk BJ, Sood AK, Herzog TJ. Latest research and treatment of advanced-stage epithelial ovarian cancer. Nat. Rev. Clin. Oncol. 2013 Apr;10(4):211-24. https://doi.org/10.1038/nrclinonc.2013.5.

Zhang W, Ou X, Wu X. Proteomics profiling of plasma exosomes in epithelial ovarian cancer: A potential role in the coagulation cascade, diagnosis and prognosis. Int. J. Oncol. 2019 Mar 7;54(5):1719-33. https://doi.org/10.3892/ijo.2019.4742.

Spuch C, Ortolano S, Navarro C. LRP-1 and LRP-2 receptors function in the membrane neuron. Trafficking mechanisms and proteolytic processing in Alzheimer's disease. Front. Physiol. 2012 Jul 16;3:269. https://doi.org/10.3389/fphys.2012.00269.

Czekay RP, Wilkins-Port CE, Higgins SP, Freytag J, Overstreet JM, Klein RM, Higgins CE, Samarakoon R, Higgins PJ. PAI-1: an integrator of cell signaling and migration. Int. J. Cell Biol. 2011;2011(1):562481. https://doi.org/10.1155/2011/562481.

Vos MC, van der Wurff AA, van Kuppevelt TH, Massuger LF. The role of MMP-14 in ovarian cancer: a systematic review. J. Ovarian Res. 2021 Dec;14:1-3. doi.org/10.1186/s13048-021-00852-7.

Boucher P, Herz J. Signaling through LRP1: Protection from atherosclerosis and beyond. Biochem. Pharmacol. 2011 Jan 1;81(1):1-5. https://doi.org/10.1016/j.bcp.2010.09.018.

Appert-Collin A, Bennasroune A, Jeannesson P, Terryn C, Fuhrmann G, Morjani H, Dedieu S. Role of LRP-1 in cancer cell migration in 3-dimensional collagen matrix. Cell Adhes. Migr. 2017 Jul 4;11(4):316-26. https://doi.org/10.1080/19336918.2016.1215788.

Feng C, Ding G, Ding Q, Wen H. Overexpression of low-density lipoprotein receptor-related protein 1 (LRP1) is associated with worsened prognosis and decreased cancer immunity in clear-cell renal cell carcinoma. Biochem. Biophys. Res. Commun. 2018 Sep 10;503(3):1537-1543. https://doi.org/10.1016/j.bbrc.2018.07.076.

Montel V, Gaultier A, Lester RD, Campana WM, Gonias SL. The low-density lipoprotein receptor–related protein regulates cancer cell survival and metastasis development. Cancer Res. 2007 Oct 15;67(20):9817-9824. https://doi.org/10.1158/0008-5472.CAN-07-0683.

Campion O, Al Khalifa T, Langlois B, Thevenard-Devy J, Salesse S, Savary K, Schneider C, Etique N, Dedieu S, Devy J. Contribution of the low-density lipoprotein receptor family to breast cancer progression. Front. Oncol. 2020 Jul 30;10:882. doi.org/10.3389/fonc.2020.00882.

Zhu M, Shen H, Wang B, He Y, Chen J, Ren J, Zhang Z, Jian X. LRP1 as a promising therapeutic target for gastrointestinal tumors: Inhibiting proliferation, invasion and migration of cancer cells. Oncol. Lett. 2023 Aug 2;26(4):1-12. https://doi.org/10.3892/ol.2023.14019.

May P, Woldt E, Matz RL, Boucher P. The LDL receptor-related protein (LRP) family: An old family of proteins with new physiological functions. Ann. Med. 2007 Jan 1;39(3):219-28. doi.org/10.1080/07853890701214881.

Jusić A, Avdić A, Hadžiavdić V, Junuzović I, Kurtčehajić D. Identification of 677C> T Polymorphism of LRP1 Gene by PCR-RFLP Method. TEM J. 2018 Nov;7(4):803-807. https://doi.org/10.18421/TEM74-17.

Fields BN. Genetic Polymorphisms in LRP1, a Newly Identified Receptor for Emerging Bunyaviruses. Doctoral dissertation. University of Pittsburgh, 2023.

Vučinić N, Stokić E, Djan I, Obreht D, Veličković N, Stankov K, Djan M. The gene polymorphism is associated with increased risk of metabolic syndrome prevalence in the Serbian population. Balkan J. Med. Genet. 2017 Jun 30;20(1):51-58. https://doi.org/10.1515/bjmg-2017-0004.

Shinohara M, Tachibana M, Kanekiyo T, Bu G. Role of LRP1 in the pathogenesis of Alzheimer’s disease: evidence from clinical and preclinical studies. J. Lipid Res. 2017 Jul;58(7):1267. https://doi.org/10.1194/jlr.R075796.

Lee JD, Hsiao KM, Chang PJ, Chen CC, Kuo YW, Huang YC, Hsu HL, Lin YH, Wu CY, Huang YC, Lee M, Hsu CY, Pan YT, Kuo CY, Lin CH. A common polymorphism decreases LRP1 mRNA stability and is associated with increased plasma factor VIII levels. Biochim. Biophys. Acta Mol. Basis Dis. 2017 Jun;1863(6):1690-1698. https://doi.org/10.1016/j.bbadis.2017.04.015.

Xing P, Liao Z, Ren Z, Zhao J, Song F, Wang G, Chen K, Yang J. Roles of low-density lipoprotein receptor-related protein 1 in tumors. Chin. J. Cancer. 2016 Jan 6;35:6. https://doi.org/10.1186/s40880-015-0064-0.

Actis Dato V, Chiabrando GA. The role of low-density lipoprotein receptor-related protein 1 in lipid metabolism, glucose homeostasis and inflammation. Int. J. Mol. Sci. 2018 Jun 15;19(6):1780. https://doi.org/10.3390/ijms19061780.

Gan M, Jiang P, McLean P, Kanekiyo T, Bu G. Low-density lipoprotein receptor-related protein 1 (LRP1) regulates the stability and function of GluA1 α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor in neurons. PloS One. 2014 Dec 12;9(12):e113237. https://doi.org/10.1371/journal.pone.0113237.

Fuentealba RA, Liu Q, Kanekiyo T, Zhang J, Bu G. Low density lipoprotein receptor-related protein 1 promotes anti-apoptotic signaling in neurons by activating Akt survival pathway. J. Biol. Chem. 2009 Dec 4;284(49):34045-34053. https://doi.org/10.1074/jbc.M109.021030.

Mantuano E, Inoue G, Li X, Takahashi K, Gaultier A, Gonias SL, Campana WM. The hemopexin domain of matrix metalloproteinase-9 activates cell signaling and promotes migration of schwann cells by binding to low-density lipoprotein receptor-related protein. J. Neurosci. 2008 Nov 5;28(45):11571-11582. https://doi.org/10.1523/JNEUROSCI.3053-08.2008.

Yancey PG, Blakemore J, Ding L, Fan D, Overton CD, Zhang Y, Linton MF, Fazio S. Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation. Arterioscler. Thromb. Vasc. Biol. 2010 Apr;30(4):787-795. https://doi.org/10.1161/ATVBAHA.109.202051.

Van Leuven F, Cassiman JJ, Van Den Berghe H. Demonstration of an alpha2-macroglobulin receptor in human fibroblasts, absent in tumor-derived cell lines. J. Biol. Chem. 1979 Jun 25;254(12):5155-5160.

Gonias SL, Campana WM. LDL receptor–related protein-1: a regulator of inflammation in atherosclerosis, cancer, and injury to the nervous system. Am. J. Pathol. 2014 Jan;184(1):18-27. https://doi.org/10.1016/j.ajpath.2013.08.029.

Pires LA, Hegg R, Freitas FR, Tavares ER, Almeida C, Baracat EC, Maranhão RC. Effect of neoadjuvant chemotherapy on low-density lipoprotein (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally advanced breast cancer. Braz. J. Med. Biol. Res. 2012 Jun;45:557-564. https://doi.org/10.1590/S0100-879X2012007500068.

Sizova O, John LS, Ma Q, Molldrem JJ. Multi-faceted role of LRP1 in the immune system. Front. Immunol. 2023 Mar 20;14:1166189. doi.org/10.3389/fimmu.2023.1166189.

Jin HR, Wang J, Wang ZJ, Xi MJ, Xia BH, Deng K, Yang JL. Lipid metabolic reprogramming in tumor microenvironment: From mechanisms to therapeutics. J. Hematol. Oncol. 2023 Sep 12;16(103). doi.org/10.1186/s13045-023-01498-2.

Mathews SG, Krishna RD, Lavanya M, Nandini K, Murali S, Agarwal P, Rani E. The Role of the Plasminogen Activator Inhibitor 1 (PAI1) in Ovarian Cancer: Mechanisms and Therapeutic Implications. Glob. Med. Genet. 2024 Dec;11(04):358-65. https://doi.org/10.1055/s-0044-1791734.

Bourazopoulou E, Kapsogeorgou EK, Routsias JG, Manoussakis MN, Moutsopoulos HM, Tzioufas AG. Functional expression of the alpha 2-macroglobulin receptor CD91 in salivary gland epithelial cells. J. Autoimmun. 2009 Sep 1;33(2):141-6. https://doi.org/10.1016/j.jaut.2009.06.004.

Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol. Rev. 2008 Jul;88(3):887-918. https://doi.org/10.1152/physrev.00033.2007.

Timilsina S, Amara AR, Abu R, Spring BQ. Identification of potential cell surface targets in patient-derived cultures toward photoimmunotherapy of high-grade serous ovarian cancer. Photochem. Photobiol. 2025 Apr 9. https://doi.org/10.1111/php.14091.

Datta A, Deng S, Gopal V, Yap KC, Halim CE, Lye ML, Ong MS, Tan TZ, Sethi G, Hooi SC, Kumar AP. Cytoskeletal dynamics in epithelial-mesenchymal transition: insights into therapeutic targets for cancer metastasis. Cancers. 2021 Apr 14;13(8):1882. https://doi.org/10.3390/cancers13081882.

Duffy AM, Bouchier-Hayes DJ, Harmey JH. Vascular endothelial growth factor (VEGF) and its role in non-endothelial cells: autocrine signalling by VEGF. In: Madame Curie Bioscience Database. Austin (TX): Landes Bioscience; 2000-2013.

Seager RJ, Hajal C, Spill F, Kamm RD, Zaman MH. Dynamic interplay between tumour, stroma and immune system can drive or prevent tumour progression. Converg. Sci. Phys. Oncol. 2017 Jul 28;3(3):034002. https://doi.org/10.1088/2057-1739/aa7e86.

Van Gool B, Dedieu S, Emonard H, Roebroek AJ. The matricellular receptor LRP1 forms an interface for signaling and endocytosis in modulation of the extracellular tumor environment. Front. Pharmacol. 2015 Nov 10;6:271. doi.org/10.3389/fphar.2015.00271.

Qu L, Wang F, Wang Y, Li Z. The regulation of LRPs by miRNAs in cancer: influencing cancer characteristics and responses to treatment. Cancer Cell Int. 2025 Dec;25(1):1-22. doi.org/10.1186/s12935-025-03804-z.

Xing P, Liu H, Xiao W, Zhang G, Zhang C, Liao Z, Li T, Yang J. The fusion gene LRP1–SNRNP25 drives invasion and migration by activating the pJNK/37LRP/MMP2 signaling pathway in osteosarcoma. Cell Death Discov. 2024 Apr 27;10(1):198. https://doi.org/10.1038/s41420-024-01962-z.

NR S, Behera MM, Naik SK, Das SK, Gopan S, Ghosh A, Sahu RN, Patra S, Purkait S. Elevated expression of cholesterol transporter LRP-1 is crucially implicated in the pathobiology of glioblastoma. Front. Neurol. 2022 Oct 4;13:1003730. https://doi.org/10.3389/fneur.2022.1003730.

Pencheva N, Tran H, Buss C, Huh D, Drobnjak M, Busam K, Tavazoie SF. Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis. Cell. 2012 Nov 21;151(5):1068-82. https://doi.org/10.1016/j.cell.2012.10.028.

Dai W, Zhou J, Chen T. Unraveling the extracellular vesicle network: insights into ovarian cancer metastasis and chemoresistance. Mol. Cancer. 2024 Sep 16;23(1):201. doi.org/10.1186/s12943-024-02103-x.

Wang Y, Zhu N, Liu J, Chen F, Song Y, Ma Y, Yang Z, Wang D. Role of tumor microenvironment in ovarian cancer metastasis and clinical advancements. J. Transl. Med. 2025 Dec;23(1):1-63. doi.org/10.1186/s12967-025-06508-0.

Xie W, Sun H, Li X, Lin F, Wang Z, Wang X. Ovarian cancer: epigenetics, drug resistance, and progression. Cancer Cell Int. 2021 Dec;21:1-6. doi.org/10.1186/s12935-021-02136-y.

Fu R, Hu R, Li W, Lv X, Zhao H, Li F. Unveiling drug resistance pathways in high-grade serous ovarian cancer (HGSOC): recent advances and future perspectives. Front. Immunol. 2025 Apr 30;16:1556377. doi.org/10.3389/fimmu.2025.1556377.

Le CC, Bennasroune A, Collin G, Hachet C, Lehrter V, Rioult D, Dedieu S, Morjani H, Appert-Collin A. LRP-1 promotes colon cancer cell proliferation in 3D collagen matrices by mediating DDR1 endocytosis. Front. Cell Dev. Biol. 2020 Jun 3;8:412. https://doi.org/10.3389/fcell.2020.00412.