Phytohormone Signaling Induces Dormancy and Apoptosis in Prostate Cancer Disseminated Tumor Cells Phytohormone Signaling in PCa Disease
Main Article Content
Abstract
Prostate cancer (PCa) remains a major health concern, ranking as the second leading cause of cancer-related deaths in men in the United States. The dissemination of tumor cells (DTCs) from the prostate, their entry into circulation, and subsequent skeletal metastasis involve complex mechanisms that are not fully elucidated. Notably, DTCs demonstrate a remarkable ability to home to the hematopoietic stem cell niche within bone marrow, where they may remain dormant for years. Key signaling pathways implicated in DTC dormancy include TGF-β, BMP4/BMP7, GAS6/TAM receptors, and Wnt5a, each influencing cell cycle arrest, survival, and phenotype adaptation. Recent research has explored analogies between dormancy mechanisms in cancer and plant biology, particularly focusing on phytohormones such as abscisic acid (ABA) and gibberellins, which regulate plant stress responses and developmental dormancy. While plants utilize PYR1/PYL/RCAR receptors for ABA, mammals rely on LANCL2 and PPARγ. This study evaluated the effects of ABA, gibberellic acid, and the ABA agonist pyrabactin on human and murine PCa cell lines. Results demonstrated that gibberellic acid lacked proliferative effects and could not counteract ABA-induced growth arrest. In contrast, pyrabactin potently induced growth arrest and apoptosis, activating SMAC/Diablo cell death pathways independently of LANCL2 and PPARγ signaling. Further, the activity of ABA and pyrabactin depended on cellular uptake via SLC4A2 and SLC4A3 anion exchangers; downregulation of these transporters partially reversed their inhibitory effects. These findings suggest a mechanistic parallel between phytohormone-induced dormancy in plants and regulated dormancy and apoptosis in PCa, opening new avenues for therapeutic targeting of dormancy pathways in cancer metastasis.
Keywords:
Prostate cancer, Disseminated Tumor Cells, Dormancy, Abscisic acid, LANCL2, PPAR Pyrabactin, SLC4A2, SLC4A3, Bone marrow microenvironment
Article Details
How to Cite
RODRIGUEZ, Agustina et al.
Phytohormone Signaling Induces Dormancy and Apoptosis in Prostate Cancer Disseminated Tumor Cells.
Medical Research Archives, [S.l.], v. 14, n. 1, jan. 2026.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7240>. Date accessed: 24 feb. 2026.
doi: https://doi.org/10.18103/mra.v14i1.7240.
Keywords
Prostate cancer, Disseminated Tumor Cells, Dormancy, Abscisic acid, LANCL2, PPAR??? Pyrabactin, SLC4A2, SLC4A3, Bone marrow microenvironment
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Shiozawa Y, Pedersen EA, Havens AM, et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. Apr 2011;121(4):1298-312. doi:10.1172 /JCI43414
4. Allocca G, Hughes R, Wang N, et al. The bone metastasis niche in breast cancer-potential overlap with the haematopoietic stem cell niche in vivo. J Bone Oncol. Aug 2019;17:100244. doi:10.1016/j. jbo.2019.100244
5. Shiozawa Y, Berry JE, Eber MR, et al. The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer. Oncotarget. May 9 2016;doi:10.18632/oncotarget.9251
6. Smith JT, Chai RC. Bone niches in the regulation of tumour cell dormancy. J Bone Oncol. Aug 2024;47:100621. doi:10.1016/j.jbo.2024.100621
7. Taichman RS, Patel LR, Bedenis R, et al. GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PLoS One. 2013; 8(4):e61873. doi:10.1371/journal.pone.0061873
8. Shiozawa Y, Pedersen EA, Patel LR, et al. GAS6/AXL axis regulates prostate cancer invasion, proliferation, and survival in the bone marrow niche 33. Neoplasia. 2010;12(2):116-127. NOT IN FILE.
9. Mishra A, Wang J, Shiozawa Y, et al. Hypoxia stabilizes GAS6/Axl signaling in metastatic prostate cancer 9. MolCancer Res. 2012;10(6):703-712.
10. Lee E, Decker AM, Cackowski FC, et al. Growth Arrest-Specific 6 (GAS6) Promotes Prostate Cancer Survival by G1 Arrest/S Phase Delay and Inhibition of Apoptotic Pathway During Chemotherapy in Bone Marrow. J Cell Biochem. May 5 2016; doi:10.1002/jcb.25582
11. Jung Y, Decker AM, Wang J, et al. Endogenous GAS6 and Mer receptor signaling regulate prostate cancer stem cells in bone marrow. Oncotarget. May 3 2016;7(18):25698-711. doi:10.18632/oncotarget.8365
12. Wang Y, Singhal U, Qiao Y, et al. Wnt Signaling Drives Prostate Cancer Bone Metastatic Tropism and Invasion. Transl Oncol. Apr 2020;13(4):100747. doi:10.1016/j.tranon.2020.100747
13. Suda T, Arai F. Wnt signaling in the niche. Cell. Mar 07 2008;132(5):729-30. doi:10.1016/j.cell.2008.02.017
14. Hall CL, Keller ET. The role of Wnts in bone metastases. Cancer Metastasis Rev. Dec 2006; 25(4):551-8. doi:10.1007/s10555-006-9022-2
15. Fleming HE, Janzen V, Lo Celso C, et al. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell. Mar 06 2008;2(3): 274-83. doi:10.1016/j.stem.2008.01.003
16. Zaid MA, Dalmizrak O, Terali K, Ozer N. Mechanistic insights into the inhibition of human placental glutathione S-transferase P1-1 by abscisic and gibberellic acids: An integrated experimental and computational study. J Mol Recognit. Sep 2023;36(9):e3050. doi:10.1002/jmr.3050
17. Chen K, Li GJ, Bressan RA, Song CP, Zhu JK, Zhao Y. Abscisic acid dynamics, signaling, and functions in plants. J Integr Plant Biol. Jan 2020;62 (1):25-54. doi:10.1111/jipb.12899
18. Cichero E, Fresia C, Guida L, et al. Identification of a high affinity binding site for abscisic acid on human lanthionine synthetase component C-like protein 2. Int J Biochem Cell Biol. Apr 2018;97:52-61. doi:10.1016/j.biocel.2018.02.003
19. Spinelli S, Begani G, Guida L, et al. LANCL1 binds abscisic acid and stimulates glucose transport and mitochondrial respiration in muscle cells via the AMPK/PGC-1alpha/Sirt1 pathway. Mol Metab. Nov 2021;53:101263. doi:10.1016/j.molmet.2021.101263
20. Gharib A, Marquez C, Meseguer-Beltran M, Sanchez-Sarasua S, Sanchez-Perez AM. Abscisic acid, an evolutionary conserved hormone: Biosynthesis, therapeutic and diagnostic applications in mammals. Biochem Pharmacol. Nov 2024;229:116521. doi:10 .1016/j.bcp.2024.116521
21. Spinelli S, Humma Z, Magnone M, Zocchi E, Sturla L. Role of Abscisic Acid in the Whole-Body Regulation of Glucose Uptake and Metabolism. Nutrients. Dec 24 2024;17(1)doi:10.3390/nu17010013
22. Spinelli S, Magnone M, Guida L, Sturla L, Zocchi E. The ABA/LANCL Hormone/Receptor System in the Control of Glycemia, of Cardiomyocyte Energy Metabolism, and in Neuroprotection: A New Ally in the Treatment of Diabetes Mellitus? Int J Mol Sci. Jan 7 2023;24(2)doi:10.3390/ijms24021199
23. Hao Q, Yin P, Yan C, et al. Functional mechanism of the abscisic acid agonist pyrabactin. J Biol Chem. Sep 10 2010;285(37):28946-52. doi:10.1074/jbc.M110.149005
24. Ueguchi-Tanaka M, Nakajima M, Motoyuki A, Matsuoka M. Gibberellin receptor and its role in gibberellin signaling in plants. Annu Rev Plant Biol. 2007;58:183-98. doi:10.1146/annurev.arplant.58.0 32806.103830
25. Hussein MM, Ali HA, Ahmed MM. Ameliorative effects of phycocyanin against gibberellic acid induced hepatotoxicity. Pestic Biochem Physiol. Mar 2015;119:28-32. doi:10.1016/j.pestbp.2015.02.010
26. Seleem AA, Hussein BHM. Synthesis and effect of a new Terbium gibberellic complex on the histopathological alteration induced by Gibberellic acid on liver and kidney of mice Mus musculus. Chem Biol Drug Des. Jul 2018;92(1):1288-1300. doi:10.1111/cbdd.13191
27. Vigliarolo T, Zocchi E, Fresia C, Booz V, Guida L. Abscisic acid influx into human nucleated cells occurs through the anion exchanger AE2. The International Journal of Biochemistry & Cell Biology. 2016/06/01/ 2016;75:99-103. doi:https://doi.org/10.1016/j.biocel.2016.03.006
28. Takahashi H, Yumoto K, Yasuhara K, et al. Anticancer polymers designed for killing dormant prostate cancer cells. Sci Rep. Jan 31 2019;9(1): 1096. doi:10.1038/s41598-018-36608-5
29. Oki T, Nishimura K, Kitaura J, et al. A novel cell-cycle-indicator, mVenus-p27K-, identifies quiescent cells and visualizes G0-G1 transition. Sci Rep. 2014;4:4012. doi:10.1038/srep04012
30. Sakaue-Sawano A, Ohtawa K, Hama H, Kawano M, Ogawa M, Miyawaki A. Tracing the silhouette of individual cells in S/G2/M phases with fluorescence. Chem Biol. Dec 22 2008;15(12):12 43-8. doi:10.1016/j.chembiol.2008.10.015
31. Nakamura-Ishizu A, Takizawa H, Suda T. The analysis, roles and regulation of quiescence in hematopoietic stem cells. Development. Dec 2014 ;141(24):4656-66. doi:10.1242/dev.106575
32. Parajuli KR, Jung Y, Taichman RS. Abscisic acid signaling through LANCL2 and PPARgamma induces activation of p38MAPK resulting in dormancy of prostate cancer metastatic cells. Oncol Rep. Mar 2024;51(3)doi:10.3892/or.2024.8698
33. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. Dec 2001;25(4):402-8. doi:10.1006/meth.2001.1262
34. Sun Y, Liu Y, Ma X, Hu H. The Influence of Cell Cycle Regulation on Chemotherapy. Int J Mol Sci. Jun 28 2021;22(13)doi:10.3390/ijms22136923
35. Ruppender NS, Morrissey C, Lange PH, Vessella RL. Dormancy in solid tumors: implications for prostate cancer. Cancer Metastasis Rev. Dec 2013;32(3-4):501-9. doi:10.1007/s10555-013-9422-z
36. Vicic I, Belev B. The pathogenesis of bone metastasis in solid tumors: a review. Croat Med J. Jun 30 2021;62(3):270-282. doi:10.3325/cmj.2021.62.270
37. Min HY, Lee HY. Cellular Dormancy in Cancer: Mechanisms and Potential Targeting Strategies. Cancer Res Treat. Jul 2023;55(3):720-736. doi:10. 4143/crt.2023.468
38. Sanchez-Sarasua S, Moustafa S, Garcia-Aviles A, et al. The effect of abscisic acid chronic treatment on neuroinflammatory markers and memory in a rat model of high-fat diet induced neuroinflammation. Nutr Metab (Lond). 2016;13: 73. doi:10.1186/s12986-016-0137-3
39. Le Page-Degivry MT, Bidard JN, Rouvier E, Bulard C, Lazdunski M. Presence of abscisic acid, a phytohormone, in the mammalian brain. Proc Natl Acad Sci U S A. Feb 1986;83(4):1155-8. doi:10.107 3/pnas.83.4.1155
40. Mukherjee A, Gaurav AK, Singh S, et al. The bioactive potential of phytohormones: A review. Biotechnol Rep (Amst). Sep 2022;35:e00748. doi:10.1016/j.btre.2022.e00748
41. Bruzzone S, Magnone M, Mannino E, et al. Abscisic Acid Stimulates Glucagon-Like Peptide-1 Secretion from L-Cells and Its Oral Administration Increases Plasma Glucagon-Like Peptide-1 Levels in Rats. PLoS One. 2015;10(10):e0140588. doi:10.1 371/journal.pone.0140588
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