Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Exogenous Expression of WNT7A in Leukemia-Derived Cell Lines Induces Resistance to Chemotherapeutic Agents

Author(s): Monserrat Alvarez-Zavala, Christian Barreto-Vargas, Luis A. Torres-Reyes, Roberto F. De la Peña-Castro, Adriana Aguilar-Lemarroy and Luis F. Jave-Suarez*

Volume 20 , Issue 12 , 2020

Page: [1504 - 1514] Pages: 11

DOI: 10.2174/1871520620666200521114100

Price: $65


Background: Dysregulations of the WNT pathway are implicated in the malignant transformation of different types of neoplasia. WNT7A is expressed in normal peripheral lymphocytes, but is decreased in the tumoral counterpart. Furthermore, the treatment of leukemic cells with recombinant WNT7A decreases proliferation, suggesting its possible use as a therapeutic biomolecule. This study aimed to evaluate the concomitant action of WNT7A and different chemotherapeutic agents over proliferation and cell death of leukemia/ lymphoma derived cell lines.

Methods: Ectopic expression of WNT7A was induced in CEM and BJAB cell lines by using a lentiviral system. RNA expression was analyzed by microarrays and qPCR, and protein expression was determined by Western Blot. Cell proliferation was measured by cell counting, metabolic activity by WST-1 assay, cell death and DNA content by flow cytometry.

Results: WNT7A ectopic expression was shown to decrease cell proliferation, but the apoptosis rate of leukemic cells was not altered. Moreover, these cells acquired resistance to doxorubicin, vincristine and MG-132. Cell cycle analysis reveals a decrease in G1 and an increase in S and G2 phases with a further upregulation of senescence- associated genes. Microarray analysis reveals that most gene expression changes were related to cancer and metabolic associated pathways. All those changes appear to be independent of the WNT canonical pathway regulation.

Conclusion: WNT7A negatively regulates cell proliferation in leukemic cell lines and promotes resistance to chemotherapeutic agents by inducing a senescence-like phenotype independently of the WNT canonical pathway.

Keywords: WNT signaling, leukemias, WNT7A, chemotherapeutic agents, senescence, cell cycle.

« Previous
Graphical Abstract
Juliusson, G.; Hough, R. Leukemia. Prog. Tumor Res., 2016, 43, 87-100.
[] [PMID: 27595359]
An, Q.; Fan, C.H.; Xu, S.M. Recent perspectives of pediatric leukemia - an update. Eur. Rev. Med. Pharmacol. Sci., 2017, 21(4)(Suppl.), 31-36.
[PMID: 29165768]
Jin, M.W.; Xu, S.M.; An, Q.; Wang, P. A review of risk factors for childhood leukemia. Eur. Rev. Med. Pharmacol. Sci., 2016, 20(18), 3760-3764.
[PMID: 27735044]
van Amerongen, R.; Nusse, R. Towards an integrated view of Wnt signaling in development. Development, 2009, 136(19), 3205-3214.
[] [PMID: 19736321]
Nusse, R.; Clevers, H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell, 2017, 169(6), 985-999.
[] [PMID: 28575679]
Duchartre, Y.; Kim, Y.M.; Kahn, M. The Wnt signaling pathway in cancer. Crit. Rev. Oncol. Hematol., 2016, 99, 141-149.
[] [PMID: 26775730]
Willert, K.; Nusse, R. Wnt proteins. Cold Spring Harb. Perspect. Biol., 2012, 4(9)a007864
[] [PMID: 22952392]
Niehrs, C. The complex world of Wnt receptor signalling. Nat. Rev. Mol. Cell Biol., 2012, 13(12), 767-779.
[] [PMID: 23151663]
Staal, F.J.; Luis, T.C.; Tiemessen, M.M. WNT signalling in the immune system: Wnt is spreading its wings. Nat. Rev. Immunol., 2008, 8(8), 581-593.
[] [PMID: 18617885]
Haybar, H.; Khodadi, E.; Shahrabi, S. Wnt/β-catenin in ischemic myocardium: interactions and signaling pathways as a therapeutic target. Heart Fail. Rev., 2019, 24(3), 411-419.
[] [PMID: 30539334]
Staal, F.J.; Chhatta, A.; Mikkers, H. Caught in a Wnt storm: Complexities of Wnt signaling in hematopoiesis. Exp. Hematol., 2016, 44(6), 451-457.
[] [PMID: 27016274]
Tiemessen, M.M.; Staal, F.J. Wnt signaling in leukemias and myeloma: T-cell factors are in control. Future Oncol., 2013, 9(11), 1757-1772.
[] [PMID: 24156335]
Seke Etet, P.F.; Vecchio, L.; Bogne Kamga, P.; Nchiwan Nukenine, E.; Krampera, M.; Nwabo Kamdje, A.H. Normal hematopoiesis and hematologic malignancies: Role of canonical Wnt signaling pathway and stromal microenvironment. Biochim. Biophys. Acta, 2013, 1835(1), 1-10.
[PMID: 22982245]
Ramos-Solano, M.; Meza-Canales, I.D.; Torres-Reyes, L.A.; Alvarez-Zavala, M.; Alvarado-Ruíz, L.; Rincon-Orozco, B.; Garcia-Chagollan, M.; Ochoa-Hernández, A.B.; Ortiz-Lazareno, P.C.; Rösl, F.; Gariglio, P.; Jave-Suárez, L.F.; Aguilar-Lemarroy, A. Expression of WNT genes in cervical cancer-derived cells: Implication of WNT7A in cell proliferation and migration. Exp. Cell Res., 2015, 335(1), 39-50.
[] [PMID: 25978974]
Huang, X.; Zhu, H.; Gao, Z.; Li, J.; Zhuang, J.; Dong, Y.; Shen, B.; Li, M.; Zhou, H.; Guo, H.; Huang, R.; Yan, J. Wnt7a activates canonical Wnt signaling, promotes bladder cancer cell invasion, and is suppressed by miR-370-3p. J. Biol. Chem., 2018, 293(18), 6693-6706.
[] [PMID: 29549123]
Kondratov, A.G.; Kvasha, S.M.; Stoliar, L.A.; Romanenko, A.M.; Zgonnyk, Y.M.; Gordiyuk, V.V.; Kashuba, E.V.; Rynditch, A.V.; Zabarovsky, E.R.; Kashuba, V.I. Alterations of the WNT7A gene in clear cell renal cell carcinomas. PLoS One, 2012, 7(10), e47012.
[] [PMID: 23056560]
Jia, B.; Qiu, X.; Chu, H.; Sun, X.; Xu, S.; Zhao, X.; Zhao, J. Wnt7a predicts poor prognosis, and contributes to growth and metastasis in tongue squamous cell carcinoma. Oncol. Rep., 2019, 41(3), 1749-1758.
[] [PMID: 30747225]
Ochoa-Hernández, A.B.; Ramos-Solano, M.; Meza-Canales, I.D.; García-Castro, B.; Rosales-Reynoso, M.A.; Rosales-Aviña, J.A.; Barrera-Chairez, E.; Ortíz-Lazareno, P.C.; Hernández-Flores, G.; Bravo-Cuellar, A.; Jave-Suarez, L.F.; Barros-Núñez, P.; Aguilar-Lemarroy, A. Peripheral T-lymphocytes express WNT7A and its restoration in leukemia-derived lymphoblasts inhibits cell proliferation. BMC Cancer, 2012, 12, 60.
[] [PMID: 22313908]
Kim, T.H.; Moon, J.Y.; Kim, S.H.; Paik, S.S.; Yoon, H.J.; Shin, D.H.; Park, S.S.; Sohn, J.W. Clinical significance of aberrant Wnt7a promoter methylation in human non-small cell lung cancer in Koreans. J. Korean Med. Sci., 2015, 30(2), 155-161.
[] [PMID: 25653486]
Yoshioka, S.; King, M.L.; Ran, S.; Okuda, H.; MacLean, J.A., II; McAsey, M.E.; Sugino, N.; Brard, L.; Watabe, K.; Hayashi, K. WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/β-catenin pathway. Mol. Cancer Res., 2012, 10(3), 469-482.
[] [PMID: 22232518]
Lan, L.; Wang, W.; Huang, Y.; Bu, X.; Zhao, C. Roles of Wnt7a in embryo development, tissue homeostasis, and human diseases. J. Cell. Biochem., 2019, 120(11), 18588-18598.
[] [PMID: 31271226]
Lin, J.B.; Sene, A.; Wiley, L.A.; Santeford, A.; Nudleman, E.; Nakamura, R.; Lin, J.B.; Moolani, H.V.; Apte, R.S. WNT7A/B promote choroidal neovascularization. Exp. Eye Res., 2018, 174, 107-112.
[] [PMID: 29864439]
Miao, N.; Bian, S.; Lee, T.; Mubarak, T.; Huang, S.; Wen, Z.; Hussain, G.; Sun, T. Opposite roles of Wnt7a and Sfrp1 in modulating proper development of neural progenitors in the mouse cerebral cortex. Front. Mol. Neurosci., 2018, 11, 247.
[] [PMID: 30065628]
Wang, Y.; Cho, C.; Williams, J.; Smallwood, P.M.; Zhang, C.; Junge, H.J.; Nathans, J. Interplay of the Norrin and Wnt7a/Wnt7b signaling systems in blood-brain barrier and blood-retina barrier development and maintenance. Proc. Natl. Acad. Sci. USA, 2018, 115(50), E11827-E11836.
[] [PMID: 30478038]
Wallace, J.; Lutgen, V.; Avasarala, S.; St Croix, B.; Winn, R.A.; Al-Harthi, L. Wnt7a induces a unique phenotype of monocyte-derived macrophages with lower phagocytic capacity and differential expression of pro- and anti-inflammatory cytokines. Immunology, 2018, 153(2), 203-213.
[] [PMID: 28872671]
Wu, D.J.; Jiang, Y.S.; He, R.Z.; Tao, L.Y.; Yang, M.W.; Fu, X.L.; Yang, J.Y.; Zhu, K. High expression of WNT7A predicts poor prognosis and promote tumor metastasis in pancreatic ductal adenocarcinoma. Sci. Rep., 2018, 8(1), 15792.
[] [PMID: 30361522]
Freese, J.L.; Pino, D.; Pleasure, S.J. Wnt signaling in development and disease. Neurobiol. Dis., 2010, 38(2), 148-153.
[] [PMID: 19765659]
Krishnamurthy, N.; Kurzrock, R. Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treat. Rev., 2018, 62, 50-60.
[] [PMID: 29169144]
Hirata, T.; Zheng, Q.; Chen, Z.; Kinoshita, H.; Okamoto, J.; Kratz, J.; Li, H.; Lui, N.; Do, H.; Cheng, T.; Tseng, H.H.; Koizumi, K.; Shimizu, K.; Zhou, H.M.; Jablons, D.; He, B. Wnt7A is a putative prognostic and chemosensitivity marker in human malignant pleural mesothelioma. Oncol. Rep., 2015, 33(4), 2052-2060.
[] [PMID: 25632963]
Thorn, C.F.; Oshiro, C.; Marsh, S.; Hernandez-Boussard, T.; McLeod, H.; Klein, T.E.; Altman, R.B. Doxorubicin pathways: Pharmacodynamics and adverse effects. Pharmacogenet. Genomics, 2011, 21(7), 440-446.
[] [PMID: 21048526]
Gan, P.P.; McCarroll, J.A.; Po’uha, S.T.; Kamath, K.; Jordan, M.A.; Kavallaris, M. Microtubule dynamics, mitotic arrest, and apoptosis: Drug-induced differential effects of betaIII-tubulin. Mol. Cancer Ther., 2010, 9(5), 1339-1348.
[] [PMID: 20442307]
Han, Y.H.; Moon, H.J.; You, B.R.; Park, W.H. The effect of MG132, a proteasome inhibitor on HeLa cells in relation to cell growth, reactive oxygen species and GSH. Oncol. Rep., 2009, 22(1), 215-221.
[PMID: 19513526]
Jiangang, T.; Xiaoguang, C.; Yuandong, F.; Liufang, G. Inhibition of WNT7A-Beta catenin signaling pathway sensitizes oral squamous cell carcinoma to cisplatin. Int. J. Clin. Exp. Pathol., 2018, 11(10), 4926-4933.
King, M.L.; Lindberg, M.E.; Stodden, G.R.; Okuda, H.; Ebers, S.D.; Johnson, A.; Montag, A.; Lengyel, E.; MacLean Ii, J.A.; Hayashi, K. WNT7A/β-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer. Oncogene, 2015, 34(26), 3452-3462.
[] [PMID: 25174399]
Ma, A.Y.; Xie, S.W.; Zhou, J.Y.; Zhu, Y. Nomegestrol acetate suppresses human endometrial cancer RL95-2 cells proliferation in vitro and in vivo possibly related to upregulating expression of SUFU and Wnt7a. Int. J. Mol. Sci., 2017, 18(7)E1337
[] [PMID: 28640224]
Bikkavilli, R.K.; Avasarala, S.; Van Scoyk, M.; Arcaroli, J.; Brzezinski, C.; Zhang, W.; Edwards, M.G.; Rathinam, M.K.; Zhou, T.; Tauler, J.; Borowicz, S.; Lussier, Y.A.; Parr, B.A.; Cool, C.D.; Winn, R.A. Wnt7a is a novel inducer of β-catenin-independent tumor-suppressive cellular senescence in lung cancer. Oncogene, 2015, 34(42), 5317-5328.
[] [PMID: 25728679]
Genescà, E.; Lazarenkov, A.; Morgades, M.; Berbis, G.; Ruíz-Xivillé, N.; Gómez-Marzo, P.; Ribera, J.; Juncà, J.; González-Pérez, A.; Mercadal, S.; Guardia, R.; Artola, M.T.; Moreno, M.J.; Martínez-López, J.; Zamora, L.; Barba, P.; Gil, C.; Tormo, M.; Cladera, A.; Novo, A.; Pratcorona, M.; Nomdedeu, J.; González-Campos, J.; Almeida, M.; Cervera, J.; Montesinos, P.; Batlle, M.; Vives, S.; Esteve, J.; Feliu, E.; Solé, F.; Orfao, A.; Ribera, J.M. Frequency and clinical impact of CDKN2A/ARF/CDKN2B gene deletions as assessed by in-depth genetic analyses in adult T cell acute lymphoblastic leukemia. J. Hematol. Oncol., 2018, 11(1), 96.
[] [PMID: 30041662]
Girardi, T.; Vicente, C.; Cools, J.; De Keersmaecker, K. The genetics and molecular biology of T-ALL. Blood, 2017, 129(9), 1113-1123.
[] [PMID: 28115373]
Gire, V.; Dulic, V. Senescence from G2 arrest, revisited. Cell Cycle, 2015, 14(3), 297-304.
[] [PMID: 25564883]
Bunz, F.; Dutriaux, A.; Lengauer, C.; Waldman, T.; Zhou, S.; Brown, J.P.; Sedivy, J.M.; Kinzler, K.W.; Vogelstein, B. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science, 1998, 282(5393), 1497-1501.
[] [PMID: 9822382]
Johmura, Y.; Shimada, M.; Misaki, T.; Naiki-Ito, A.; Miyoshi, H.; Motoyama, N.; Ohtani, N.; Hara, E.; Nakamura, M.; Morita, A.; Takahashi, S.; Nakanishi, M. Necessary and sufficient role for a mitosis skip in senescence induction. Mol. Cell, 2014, 55(1), 73-84.
[] [PMID: 24910096]
García-Castro, B.; Alvarez-Zavala, M.; Riveros-Magaña, A.R.; Ortíz-Lazareno, P.C.; Ratkovich-González, S.; Hernández-Flores, G.; Bravo-Cuellar, A.; Jave-Suarez, L.F.; Aguilar-Lemarroy, A. Restoration of WNT4 inhibits cell growth in leukemia-derived cell lines. BMC Cancer, 2013, 13, 557.
[] [PMID: 24274766]
Nemeth, M.J.; Topol, L.; Anderson, S.M.; Yang, Y.; Bodine, D.M. Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation. Proc. Natl. Acad. Sci. USA, 2007, 104(39), 15436-15441.
[] [PMID: 17881570]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy