Abstract
The natural product Honokiol exhibits robust antitumor activity against a range of cancers, and it has also received approval to undergo phase I clinical trial testing. We confrmed that honokiol can promote the apoptotic death of tumor cells through cell experiments. Then siRNA constructs specific for PIAS3, PIAS3 overexpression plasmid and the mutation of the STAT3 Tyr705 residue were used to confirm the mechanism of Honokiol-induced apoptosis. Finally, we confrmed that honokiol can promote PIAS3 upregulation, in turn suppressing STAT3 Tyr705 phosphorylation through the in vivo and in vitro experiments. Honokiol was ultimately found to reduce tumor cell viability by promoting apoptosis through a mechanism dependent on the ability of Honokiol to promote PIAS3 upregulation and the selective inhibition of p-STAT3 (Tyr705) without affecting p-STAT3 (Ser727) or p-STAT1 (Tyr701) levels. PIAS3 knockdown and overexpression in tumor cells altered STAT3 activation and associated DNA binding activity through the control of Tyr705 phosphorylation via PIAS3-STAT3 complex formation, ultimately shaping Honokiol-induced tumor cell apoptosis. Honokiol was also confirmed to significantly prolong the survival of mice bearing xenograft tumors in a PIAS3-dependent fashion. Together, these findings highlight a novel pathway through which Honokiol can promote PIAS3 upregulation, in turn suppressing STAT3 Tyr705 phosphorylation and promoting the apoptotic death of tumor cells.
Similar content being viewed by others
References
Khatoon F et al (2023) Pharmacological features, health benefits and clinical implications of honokiol. J Biomol Struct Dyn 41(15):7511–7533
Wang X et al (2014) Honokiol enhances paclitaxel efficacy in multi-drug resistant human cancer model through the induction of apoptosis. PLoS ONE 9(2):e86369
Ishitsuka K et al (2005) Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis. Blood 106(5):1794–1800
Hahm ER et al (2008) Honokiol, a constituent of oriental medicinal herb magnolia officinalis, inhibits growth of PC-3 xenografts in vivo in association with apoptosis induction. Clin Cancer Res 14(4):1248–1257
Shigemura K et al (2007) Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells. Cancer 109(7):1279–1289
Liu H et al (2008) Anti-tumor effect of honokiol alone and in combination with other anti-cancer agents in breast cancer. Eur J Pharmacol 591(1–3):43–51
Zou Y et al (2018) Synergistically enhanced antimetastasis effects by honokiol-loaded pH-sensitive polymer-doxorubicin conjugate micelles. ACS Appl Mater Interfaces 10(22):18585–18600
Chio CC et al (2018) Honokiol enhances temozolomide-induced apoptotic insults to malignant glioma cells via an intrinsic mitochondrion-dependent pathway. Phytomedicine 49:41–51
Wang Z et al (2017) Concurrently suppressing multidrug resistance and metastasis of breast cancer by co-delivery of paclitaxel and honokiol with pH-sensitive polymeric micelles. Acta Biomater 62:144–156
Wang X et al (2018) Honokiol radiosensitizes squamous cell carcinoma of the head and neck by downregulation of survivin. Clin Cancer Res 24(4):858–869
Hu J et al (2008) Liposomal honokiol, a potent anti-angiogenesis agent, in combination with radiotherapy produces a synergistic antitumor efficacy without increasing toxicity. Exp Mol Med 40(6):617–628
Banik K et al (2019) Honokiol for cancer therapeutics: a traditional medicine that can modulate multiple oncogenic targets. Pharmacol Res 144:192–209
Muniraj N et al (2020) Induction of STK11-dependent cytoprotective autophagy in breast cancer cells upon honokiol treatment. Cell Death Discov 6:81
Ponnurangam S et al (2012) Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells. Mol Cancer Ther 11(4):963–972
Leeman-Neill RJ et al (2010) Honokiol inhibits epidermal growth factor receptor signaling and enhances the antitumor effects of epidermal growth factor receptor inhibitors. Clin Cancer Res 16(9):2571–2579
Liu X et al (2021) Honokiol induces paraptosis-like cell death of acute promyelocytic leukemia via mTOR & MAPK signaling pathways activation. Apoptosis 26(3–4):195–208
Yeh PS et al (2016) Honokiol induces autophagy of neuroblastoma cells through activating the PI3K/Akt/mTOR and endoplasmic reticular stress/ERK1/2 signaling pathways and suppressing cell migration. Cancer Lett 370(1):66–77
Qiu L et al (2015) Honokiol ameliorates endothelial dysfunction through suppression of PTX3 expression, a key mediator of IKK/IkappaB/NF-kappaB, in atherosclerotic cell model. Exp Mol Med 47(7):e171
Battle TE, Arbiser J, Frank DA (2005) The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Blood 106(2):690–697
Huang JS et al (2016) Honokiol inhibits sphere formation and xenograft growth of oral cancer side population cells accompanied with JAK/STAT signaling pathway suppression and apoptosis induction. BMC Cancer 16:245
Philips RL et al (2022) The JAK-STAT pathway at 30: much learned, much more to do. Cell 185(21):3857–3876
Hu X et al (2021) The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther 6(1):402
O’Shea JJ, Holland SM, Staudt LM (2013) JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 368(2):161–170
Waldmann TA, Chen J (2017) Disorders of the JAK/STAT pathway in T Cell lymphoma pathogenesis: implications for immunotherapy. Annu Rev Immunol 35:533–550
Sengupta S et al (2017) Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic stat3. Oncogene 36(41):5709–5721
Rajendran P et al (2012) Honokiol inhibits signal transducer and activator of transcription-3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP-1. J Cell Physiol 227(5):2184–2195
Wang Y et al (2014) GdX/UBL4A specifically stabilizes the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis. Mol Cell 53(5):752–765
Chung CD et al (1997) Specific inhibition of stat3 signal transduction by PIAS3. Science 278(5344):1803–1805
Han Y et al (2006) Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma. Blood 108(8):2796–2803
Mohan CD et al (2022) Targeting STAT3 signaling pathway in cancer by agents derived from mother nature. Semin Cancer Biol 80:157–182
Levy DE, Darnell JE Jr (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3(9):651–662
Ernst M et al (2008) STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J Clin Invest 118(5):1727–1738
Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809
Pillai VB et al (2015) Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial sirt3. Nat Commun 6:6656
Avtanski DB et al (2014) Honokiol inhibits epithelial-mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis. Mol Oncol 8(3):565–580
Fan Y et al (2018) Honokiol eliminates glioma/glioblastoma stem cell-like cells via JAK-STAT3 signaling and inhibits tumor progression by targeting epidermal growth factor receptor. Cancers (Basel) 11(1):22
Pulivendala G, Bale S, Godugu C (2020) Honokiol: a polyphenol neolignan ameliorates pulmonary fibrosis by inhibiting TGF-beta/Smad signaling, matrix proteins and IL-6/CD44/STAT3 axis both in vitro and in vivo. Toxicol Appl Pharmacol 391:114913
Funding
This study was supported by National Natural Science Foundation of China grant (81402945), Tianjin Key Medical Discipline (Specialty) Construction Project grant (TJYXZDXK-009A), and Tianjin Research Innovation Project for postgraduate students (2021YJSB265).
Author information
Authors and Affiliations
Contributions
Formal analysis, Writing-Original Draft, YF; Data Curation, Conceptualization, XZ; Visualization, Data Curation, XW; Methodology, SM; Software, Validation, YS; Validation, JK; Methodology, XL; Data Curation, ZS; Supervision, Resources, LL; Formal analysis, Investigation, LQ; Writing—Review & Editing, ZQ; Project administration, SZ; Supervision, XL; Supervision, Funding acquisition, HZ; Conceptualization, Supervision, Project administration, Writing-Review and Editing, XW. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interests
The authors declare that they have no confict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Fei, Y., Zhang, X., Wang, X. et al. Upregulation of tumor suppressor PIAS3 by Honokiol promotes tumor cell apoptosis via selective inhibition of STAT3 tyrosine 705 phosphorylation. J Nat Med 78, 285–295 (2024). https://doi.org/10.1007/s11418-023-01757-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11418-023-01757-z