Notch Signaling in Prostate Cancer: Refining a Therapeutic Opportunity

Overview

Journal Histol Histopathol

Specialties Anatomy & Histology
Pathology

Date 2015 Nov 3

PMID 26521657

Citations 22

Authors

Qingtai Su

Li Xin

Affiliations

Soon will be listed here.

Abstract

Notch is an evolutionarily conserved signaling pathway that plays a critical role in specifying cell fate and regulating tissue homeostasis and carcinogenesis. Studies using organ cultures and genetically engineered mouse models have demonstrated that Notch signaling regulates prostate development and homeostasis. However, the role of the Notch signaling pathway in prostate cancer remains inconclusive. Many published studies have documented consistent deregulation of major Notch signaling components in human prostate cancer cell lines, mouse models for prostate cancers, and human prostate cancer specimens at both the mRNA and the protein levels. However, functional studies in human cancer cells by modulation of Notch pathway elements suggest both tumor suppressive and oncogenic roles of Notch. These controversies may originate from our inadequate understanding of the regulation of Notch signaling under versatile genetic contexts, and reflect the multifaceted and pleiotropic roles of Notch in regulating different aspects of prostate cancer cell biology, such as proliferation, metastasis, and chemo-resistance. Future comprehensive studies using various mouse models for prostate cancer may help clarify the role of Notch signaling in prostate cancer and provide a solid basis for determining whether and how Notch should be employed as a therapeutic target for prostate cancer.

Citing Articles

3-Acetyl-11-keto-β-boswellic acid (AKBA) induced antiproliferative effect by suppressing Notch signaling pathway and synergistic interaction with cisplatin against prostate cancer cells.

Verma M, Fatima S, Syed A, Elgorban A, Abid I, Shing Wong L Naunyn Schmiedebergs Arch Pharmacol. 2025; .

PMID: 39985578 DOI: 10.1007/s00210-025-03899-1.

Epithelial-mesenchymal plasticity in cancer: signaling pathways and therapeutic targets.

Wang X, Xue X, Pang M, Yu L, Qian J, Li X MedComm (2020). 2024; 5(8):e659.

PMID: 39092293 PMC: 11292400. DOI: 10.1002/mco2.659.

Anti-prostate cancer mechanism of black ginseng during the "nine steaming and nine sun-drying" process based on HPLC analysis combined with vector space network pharmacology.

Zhang Y, Huang Y, Dou D Discov Oncol. 2024; 15(1):12.

PMID: 38236377 PMC: 10796871. DOI: 10.1007/s12672-024-00862-z.

Emerging proteins involved in castration‑resistant prostate cancer via the AR‑dependent and AR‑independent pathways (Review).

Feng K, Liu C, Wang W, Kong P, Tao Z, Liu W Int J Oncol. 2023; 63(5).

PMID: 37732538 PMC: 10609492. DOI: 10.3892/ijo.2023.5575.

MiR-146b-5p/SEMA3G regulates epithelial-mesenchymal transition in clear cell renal cell carcinoma.

Tang M, Xiong T Cell Div. 2023; 18(1):4.

PMID: 36882799 PMC: 9993666. DOI: 10.1186/s13008-023-00083-w.

References

Ntziachristos P, Lim J, Sage J, Aifantis I . From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell. 2014; 25(3):318-34. PMC: 4040351. DOI: 10.1016/j.ccr.2014.02.018. View

Mazzone M, Selfors L, Albeck J, Overholtzer M, Sale S, Carroll D . Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proc Natl Acad Sci U S A. 2010; 107(11):5012-7. PMC: 2841923. DOI: 10.1073/pnas.1000896107. View

Fitzgerald K, Harrington A, Leder P . Ras pathway signals are required for notch-mediated oncogenesis. Oncogene. 2000; 19(37):4191-8. DOI: 10.1038/sj.onc.1203766. View

Rose S, Kunnimalaiyaan M, Drenzek J, Seiler N . Notch 1 signaling is active in ovarian cancer. Gynecol Oncol. 2010; 117(1):130-3. DOI: 10.1016/j.ygyno.2009.12.003. View

Robinson D, Kalyana-Sundaram S, Wu Y, Shankar S, Cao X, Ateeq B . Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nat Med. 2011; 17(12):1646-51. PMC: 3233654. DOI: 10.1038/nm.2580. View

Villaronga M, Bevan C, Belandia B . Notch signaling: a potential therapeutic target in prostate cancer. Curr Cancer Drug Targets. 2008; 8(7):566-80. DOI: 10.2174/156800908786241096. View

Sharma A, Gadkari R, Ramakanth S, Padmanabhan K, Madhumathi D, Devi L . A novel Monoclonal Antibody against Notch1 Targets Leukemia-associated Mutant Notch1 and Depletes Therapy Resistant Cancer Stem Cells in Solid Tumors. Sci Rep. 2015; 5:11012. PMC: 4457015. DOI: 10.1038/srep11012. View

Hahm E, Chandra-Kuntal K, Desai D, Amin S, Singh S . Notch activation is dispensable for D, L-sulforaphane-mediated inhibition of human prostate cancer cell migration. PLoS One. 2012; 7(9):e44957. PMC: 3436754. DOI: 10.1371/journal.pone.0044957. View

Alana L, Sese M, Canovas V, Punyal Y, Fernandez Y, Abasolo I . Prostate tumor OVerexpressed-1 (PTOV1) down-regulates HES1 and HEY1 notch targets genes and promotes prostate cancer progression. Mol Cancer. 2014; 13:74. PMC: 4021398. DOI: 10.1186/1476-4598-13-74. View

10.

Karthaus W, Iaquinta P, Drost J, Gracanin A, van Boxtel R, Wongvipat J . Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell. 2014; 159(1):163-175. PMC: 4772677. DOI: 10.1016/j.cell.2014.08.017. View

11.

Hudson R, Yi M, Esposito D, Watkins S, Hurwitz A, Yfantis H . MicroRNA-1 is a candidate tumor suppressor and prognostic marker in human prostate cancer. Nucleic Acids Res. 2012; 40(8):3689-703. PMC: 3333883. DOI: 10.1093/nar/gkr1222. View

12.

Gao D, Vela I, Sboner A, Iaquinta P, Karthaus W, Gopalan A . Organoid cultures derived from patients with advanced prostate cancer. Cell. 2014; 159(1):176-187. PMC: 4237931. DOI: 10.1016/j.cell.2014.08.016. View

13.

Xin L, Lukacs R, Lawson D, Cheng D, Witte O . Self-renewal and multilineage differentiation in vitro from murine prostate stem cells. Stem Cells. 2007; 25(11):2760-9. DOI: 10.1634/stemcells.2007-0355. View

14.

Pear W, Aster J, Scott M, Hasserjian R, Soffer B, Sklar J . Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med. 1996; 183(5):2283-91. PMC: 2192581. DOI: 10.1084/jem.183.5.2283. View

15.

Wu X, Xu K, Zhang L, Deng Y, Lee P, Shapiro E . Differentiation of the ductal epithelium and smooth muscle in the prostate gland are regulated by the Notch/PTEN-dependent mechanism. Dev Biol. 2011; 356(2):337-49. PMC: 3152294. DOI: 10.1016/j.ydbio.2011.05.659. View

16.

Weng A, Ferrando A, Lee W, Morris 4th J, Silverman L, Sanchez-Irizarry C . Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004; 306(5694):269-71. DOI: 10.1126/science.1102160. View

17.

Takeuchi H, Haltiwanger R . Significance of glycosylation in Notch signaling. Biochem Biophys Res Commun. 2014; 453(2):235-42. PMC: 4254162. DOI: 10.1016/j.bbrc.2014.05.115. View

18.

Kandachar V, Roegiers F . Endocytosis and control of Notch signaling. Curr Opin Cell Biol. 2012; 24(4):534-40. PMC: 3425709. DOI: 10.1016/j.ceb.2012.06.006. View

19.

Jhappan C, Gallahan D, Stahle C, Chu E, Smith G, Merlino G . Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev. 1992; 6(3):345-55. DOI: 10.1101/gad.6.3.345. View

20.

Wang Z, Li Y, Ahmad A, Banerjee S, Azmi A, Kong D . Down-regulation of Notch-1 is associated with Akt and FoxM1 in inducing cell growth inhibition and apoptosis in prostate cancer cells. J Cell Biochem. 2010; 112(1):78-88. PMC: 3792569. DOI: 10.1002/jcb.22770. View