AccScience Publishing / GPD / Online First / DOI: 10.36922/gpd.0658
Submit to GPD
Cite this article
105
Download
2747
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Verteporfin induces YAP-dependent cell cycle arrest and caspase-mediated cellular apoptosis in triple-negative breast cancer cells

Sulfath Thottungal Parambil1 ,  Gisha Rose Antony1 ,  Ajeesh Babu Littleflower1 ,  Lakshmi Subhadradevi1*
Show Less
1 Laboratory of Molecular Medicine, Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, India
GPD 2023, 2(2), 0658 https://doi.org/10.36922/gpd.0658
Submitted: 19 April 2023 | Accepted: 26 June 2023 | Published: 7 July 2023
© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
Cite
XML
Abstract

Triple-negative breast cancer (TNBC) subtype endows distinctive biological features, including aberrant proliferation, and deducing the molecular mechanism harmonizing the TNBC characteristics is crucial for a greater understanding and prognosis of the disease. The aim of the present study was to analyze the anti-tumorigenic effects of verteporfin (VP) in TNBC in vitro. We evaluated the tumorigenic properties of TNBC cells on VP treatment to assess the cell viability, apoptosis, cell cycle, cell survival, and protein/mRNA expressions in MDA-MB-231 and SUM-159 breast cancer cells. Transient silencing of yes-associated protein (YAP) was performed to validate the data. TNBC cells exhibited a comparatively higher active YAP downstream signaling, and VP resulted in the nuclear exclusion of YAP to a significant extent. VP inhibits the proliferation of TNBC cells by altering cyclin-dependent kinase inhibitors, thereby rendering cellular arrest at the G0/G1 phase. In a dose-dependent manner, VP induces the apoptotic machinery in TNBC cells. Moreover, transient silencing of YAP in TNBC cells exhibited a similar pattern of antiproliferative effects. Elevated YAP nuclear activity and downstream signaling in TNBC are associated with sustaining the proliferative capacity of the cells by inhibiting cellular apoptosis. VP induces antiproliferative effects on TNBC through cytoplasmic retention of YAP. Consequently, cells rewire the course of the cell cycle and stimulate cellular death. We suggest YAP signaling as a prerequisite for TNBC cell progression, and VP without light activation exerts anti-tumorigenic effects on TNBC cells.

Keywords
Verteporfin
Triple-negative breast cancer
Yes-associated protein
Cell cycle
Hippo signaling
Funding
DBT-India
Fellowship grant from ICMR
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
References
  1. Perou CM, Sørlie T, Eisen MB, et al., 2000, Molecular portraits of human breast tumours. Nature, 406(6797): 747–752. https://doi.org/10.1038/35021093

 

  1. Maqbool M, Bekele F, Fekadu G, 2022, Treatment strategies against triple-negative breast cancer: An updated review. Breast Cancer (Dove Med Press), 14: 15–24. https://doi.org/10.2147/BCTT.S348060

 

  1. Yin L, Duan JJ, Bian XW, et al., 2020, Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res, 22: 61. https://doi.org/10.1186/s13058-020-01296-5

 

  1. Chang-Qing Y, Jie L, Shi-Qi Z, et al., 2020, Recent treatment progress of triple negative breast cancer. Prog Biophys Mol Biol, 151: 40–53. https://doi.org/10.1016/j.pbiomolbio.2019.11.007

 

  1. Edgar BA, 2006, From cell structure to transcription: Hippo forges a new path. Cell, 124(2): 267–273. https://doi.org/10.1016/j.cell.2006.01.005

 

  1. Saucedo LJ, Edgar BA, 2007, Filling out the Hippo pathway. Nat Rev Mol Cell Biol, 8(8): 613–621. https://doi.org/10.1038/nrm2221

 

  1. Poma AM, Torregrossa L, Bruno R, et al., 2018, Hippo pathway affects survival of cancer patients: Extensive analysis of TCGA data and review of literature. Sci Rep, 8(1): 10623. https://doi.org/10.1038/s41598-018-28928-3

 

  1. Schütte U, Bisht S, Heukamp LC, et al., 2014, Hippo signaling mediates proliferation, invasiveness, and metastatic potential of clear cell renal cell carcinoma. Transl Oncol, 7(2): 309–321. https://doi.org/10.1016/j.tranon.2014.02.005

 

  1. Choi W, Kim J, Park J, et al., 2018, YAP/TAZ initiates gastric tumorigenesis via upregulation of MYC. Cancer Res, 78(12): 3306–3320. https://doi.org/10.1158/0008-5472.CAN-17-3487

 

  1. Kim HM, Jung WH, Koo JS, 2015, Expression of Yes-associated protein (YAP) in metastatic breast cancer. Int J Clin Exp Pathol, 8(9): 11248–11257.

 

  1. Yuan M, Tomlinson V, Lara R, et al., 2008, Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ, 15(11): 1752–1759. https://doi.org/10.1038/cdd.2008.108

 

  1. Tufail R, Jorda M, Zhao W, et al., 2012, Loss of Yes-associated protein (YAP) expression is associated with estrogen and progesterone receptors negativity in invasive breast carcinomas. Breast Cancer Res Treat, 131: 743–750. https://doi.org/10.1007/s10549-011-1435-0

 

  1. Wu L, Yang X, 2018, Targeting the Hippo pathway for breast cancer therapy. Cancers (Basel), 10(11): 422. https://doi.org/10.3390/cancers10110422

 

  1. Wang Z, Kong Q, Su P, et al., 2020, Regulation of Hippo signaling and triple negative breast cancer progression by an ubiquitin ligase RNF187. Oncogenesis, 9(3): 36. https://doi.org/10.1038/s41389-020-0220-5

 

  1. Schmidt-Erfurth U, Hasan T, 2000, Mechanisms of action of photodynamic therapy with verteporfin for the treatment of age-related macular degeneration. Surv Ophthalmol, 45(3): 195–214. https://doi.org/10.1016/S0039-6257(00)00158-2

 

  1. Richter A, Sternberg E, Waterfield E, et al., 1989, Characterization of Benzoporphyrin Derivative, A New Photosensitizer. In: Proceedings of the Society of Photo- Optical Instrumentation Engineers (SPIE), Advances in Photochemotherapy. Vol. 997. p132-138. https://doi.org/10.1117/12.960196

 

  1. Fingar VH, Kik PK, Haydon PS, et al., 1999, Analysis of acute vascular damage after photodynamic therapy using benzoporphyrin derivative (BPD). Br J Cancer, 79(11): 1702–1708. https://doi.org/10.1038/sj.bjc.6690271

 

  1. Liu-Chittenden Y, Huang B, Shim JS, et al., 2012, Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev, 26(12): 1300–1305. https://doi.org/10.1101/gad.192856.112

 

  1. Al-Moujahed A, Brodowska K, Stryjewski TP, et al., 2017, Verteporfin inhibits growth of human glioma in vitro without light activation. Sci Rep, 7(1): 7602. https://doi.org/10.1038/s41598-017-07632-8

 

  1. Ma YW, Liu YZ, Pan JX, 2016, Verteporfin induces apoptosis and eliminates cancer stem-like cells in uveal melanoma in the absence of light activation. Am J Cancer Res, 6(12): 2816–2830.

 

  1. Gibault F, Bailly F, Corvaisier M, et al., 2017, Molecular features of the YAP inhibitor verteporfin: Synthesis of hexasubstituted dipyrrins as potential inhibitors of YAP/ TAZ, the downstream effectors of the Hippo pathway. ChemMedChem, 12(12): 954–961. https://doi.org/10.1002/cmdc.201700063

 

  1. Pan W, Wang Q, Zhang Y, et al., 2016, Verteporfin can reverse the paclitaxel resistance induced by YAP over-expression in HCT-8/T cells without photoactivation through inhibiting YAP expression. Cell Physiol Biochem, 39(2): 481–490. https://doi.org/10.1159/000445640

 

  1. Wang C, Zhu X, Feng W, et al., 2016, Verteporfin inhibits YAP function through up-regulating 14-3-3σ sequestering YAP in the cytoplasm. Am J Cancer Res, 6(1): 27–37.

 

  1. Brodowska K, Al-Moujahed A, Marmalidou A, et al., 2014, The clinically used photosensitizer Verteporfin (VP) inhibits YAP-TEAD and human retinoblastoma cell growth in vitro without light activation. Exp Eye Res, 124: 67–73. https://doi.org/10.1016/j.exer.2014.04.011

 

  1. Wei C, Li X, 2020, Verteporfin inhibits cell proliferation and induces apoptosis in different subtypes of breast cancer cell lines without light activation. BMC Cancer, 20: 1042. https://doi.org/10.1186/s12885-020-07555-0

 

  1. Wei C, Li X, 2020, Determination of the migration effect and molecular docking of verteporfin in different subtypes of breast cancer cells. Mol Med Rep, 22(5): 3955–3961. https://doi.org/10.3892/mmr.2020.11482

 

  1. Feng J, Gou J, Jia J, et al., 2016, Verteporfin, a suppressor of YAP-TEAD complex, presents promising antitumor properties on ovarian cancer. Onco Targets Ther, 9: 5371–5381. https://doi.org/10.2147/OTT.S109979

 

  1. Huang Y, Ahmad US, Rehman A, et al., 2022, YAP inhibition by verteporfin causes downregulation of desmosomal genes and proteins leading to the disintegration of intercellular junctions. Life (Basel), 12(6): 792. https://doi.org/10.3390/life12060792

 

  1. Musgrove EA, Lee CS, Buckley MF, et al., 1994, Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. Proc Natl Acad Sci U S A, 91(17): 8022–8026. https://doi.org/10.1073/pnas.91.17.8022

 

  1. Toyoshima H, Hunter T, 1994, P27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell, 78(1): 67–74. https://doi.org/10.1016/0092-8674(94)90573-8

 

  1. Askew D, Ashmun RA, Simmons BC, et al., 1991, Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene, 6(10): 1915–1922.

 

  1. Nishimoto M, Uranishi K, Asaka MN, et al., 2019, Transformation of normal cells by aberrant activation of YAP via cMyc with TEAD. Sci Rep, 9(1): 10933. https://doi.org/10.1038/s41598-019-47301-6

 

  1. Huang J, Wu S, Barrera J, et al., 2005, The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell, 122(3): 421–434. https://doi.org/10.1016/j.cell.2005.06.007

 

  1. Andrade D, Mehta M, Griffith J, et al., 2017, YAP1 inhibition radiosensitizes triple negative breast cancer cells by targeting the DNA damage response and cell survival pathways. Oncotarget, 8(58): 98495–98508. https://doi.org/10.18632/oncotarget.21913
Share
Back to top
Gene & Protein in Disease, Electronic ISSN: 2811-003X Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept