Beta-Lapachone Attenuates BMSC-Mediated Neuroblastoma Malignant Transformation by Inhibiting Gal-3/Gal-3BP/IL6 Axis

Overview

Journal Front Pharmacol

Date 2021 Nov 18

PMID 34790130

Citations 2

Authors

Yang Zhou

Hui Yan

Qiang Zhou

Ruiling Feng

Penggao Wang

Fang Yang

Yaodong Zhang

Ziqiao Yuan

Bo Zhai

Affiliations

Soon will be listed here.

Abstract

The inflammatory factor IL6 secreted by bone marrow mesenchymal stem cells (BMSCs) in the tumor microenvironment (TME) facilitates the survival and therapeutic resistance of neuroblastoma (NB). Here, we found that IL6 expression in primary tumor tissues or bone marrow (BM) metastases was closely associated with the disease risk and prognosis of NB patients. IL6 secretion from immortalized BMSC (iBMSC) was directly regulated by NB cells and is involved in promoting the proliferation and metastasis of NB cells. Beta-Lapachone (ARQ-501, LPC), an -naphthoquinone natural product, significantly prevented the iBMSC-induced malignant transformation effect on NB cells through suppressing the expression and secretion of IL6 from iBMSC and . Mechanistically, LPC disrupted the crosstalk between NB cells and iBMSC in an NQO1-dependent manner through blocking the Gal-3/Gal-3BP/IL6 axis. Our results reveal the effect of iBMSC-derived IL6 on TME-induced malignant transformation of NB cells, and provide theoretical basis for the clinical application of LPC as a potential IL6 inhibitor in high-risk refractory NB patients.

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References

Monclair T, Brodeur G, Ambros P, Brisse H, Cecchetto G, Holmes K . The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol. 2008; 27(2):298-303. PMC: 2650389. DOI: 10.1200/JCO.2008.16.6876. View

Bey E, Bentle M, Reinicke K, Dong Y, Yang C, Girard L . An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Proc Natl Acad Sci U S A. 2007; 104(28):11832-7. PMC: 1913860. DOI: 10.1073/pnas.0702176104. View

Rickman D, Schulte J, Eilers M . The Expanding World of N-MYC-Driven Tumors. Cancer Discov. 2018; 8(2):150-163. DOI: 10.1158/2159-8290.CD-17-0273. View

Gong Q, Hu J, Wang P, Li X, Zhang X . A comprehensive review on β-lapachone: Mechanisms, structural modifications, and therapeutic potentials. Eur J Med Chem. 2020; 210:112962. DOI: 10.1016/j.ejmech.2020.112962. View

Blanco E, Bey E, Dong Y, Weinberg B, Sutton D, Boothman D . Beta-lapachone-containing PEG-PLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells. J Control Release. 2007; 122(3):365-74. PMC: 2064869. DOI: 10.1016/j.jconrel.2007.04.014. View

Ara T, Song L, Shimada H, Keshelava N, Russell H, Metelitsa L . Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells. Cancer Res. 2009; 69(1):329-37. PMC: 2761219. DOI: 10.1158/0008-5472.CAN-08-0613. View

Quinn C, Beierle A, Beierle E . Artificial Tumor Microenvironments in Neuroblastoma. Cancers (Basel). 2021; 13(7). PMC: 8037559. DOI: 10.3390/cancers13071629. View

Asgharzadeh S, Salo J, Ji L, Oberthuer A, Fischer M, Berthold F . Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma. J Clin Oncol. 2012; 30(28):3525-32. PMC: 3675667. DOI: 10.1200/JCO.2011.40.9169. View

Blavier L, Yang R, DeClerck Y . The Tumor Microenvironment in Neuroblastoma: New Players, New Mechanisms of Interaction and New Perspectives. Cancers (Basel). 2020; 12(10). PMC: 7599920. DOI: 10.3390/cancers12102912. View

10.

James S, Fox J, Afsari F, Lee J, Clough S, Knight C . Multiparameter Analysis of Human Bone Marrow Stromal Cells Identifies Distinct Immunomodulatory and Differentiation-Competent Subtypes. Stem Cell Reports. 2015; 4(6):1004-15. PMC: 4471830. DOI: 10.1016/j.stemcr.2015.05.005. View

11.

Park J, Lee Y, Kim J, Seo H, Kim H . β-Lapachone increases phase II antioxidant enzyme expression via NQO1-AMPK/PI3K-Nrf2/ARE signaling in rat primary astrocytes. Free Radic Biol Med. 2016; 97:168-178. DOI: 10.1016/j.freeradbiomed.2016.05.024. View

12.

Gupta D, Podar K, Tai Y, Lin B, Hideshima T, Akiyama M . beta-lapachone, a novel plant product, overcomes drug resistance in human multiple myeloma cells. Exp Hematol. 2002; 30(7):711-20. DOI: 10.1016/s0301-472x(02)00839-1. View

13.

Egler R, Burlingame S, Nuchtern J, Russell H . Interleukin-6 and soluble interleukin-6 receptor levels as markers of disease extent and prognosis in neuroblastoma. Clin Cancer Res. 2008; 14(21):7028-34. PMC: 2613275. DOI: 10.1158/1078-0432.CCR-07-5017. View

14.

Ara T, Nakata R, Sheard M, Shimada H, Buettner R, Groshen S . Critical role of STAT3 in IL-6-mediated drug resistance in human neuroblastoma. Cancer Res. 2013; 73(13):3852-64. PMC: 3740971. DOI: 10.1158/0008-5472.CAN-12-2353. View

15.

Nakata R, Shimada H, Fernandez G, Fanter R, Fabbri M, Malvar J . Contribution of neuroblastoma-derived exosomes to the production of pro-tumorigenic signals by bone marrow mesenchymal stromal cells. J Extracell Vesicles. 2017; 6(1):1332941. PMC: 5505006. DOI: 10.1080/20013078.2017.1332941. View

16.

Gomes C, de Albuquerque Wanderley Sales V, Gomes de Melo C, Ferreira da Silva R, Hideki Vicente Nishimura R, Rolim L . Beta-lapachone: Natural occurrence, physicochemical properties, biological activities, toxicity and synthesis. Phytochemistry. 2021; 186:112713. DOI: 10.1016/j.phytochem.2021.112713. View

17.

Borriello L, Seeger R, Asgharzadeh S, DeClerck Y . More than the genes, the tumor microenvironment in neuroblastoma. Cancer Lett. 2015; 380(1):304-14. PMC: 5558454. DOI: 10.1016/j.canlet.2015.11.017. View

18.

Fukaya Y, Shimada H, Wang L, Zandi E, DeClerck Y . Identification of galectin-3-binding protein as a factor secreted by tumor cells that stimulates interleukin-6 expression in the bone marrow stroma. J Biol Chem. 2008; 283(27):18573-81. DOI: 10.1074/jbc.M803115200. View

19.

Shen A, Kim H, Oh G, Lee S, Lee S, Pandit A . NAD augmentation ameliorates acute pancreatitis through regulation of inflammasome signalling. Sci Rep. 2017; 7(1):3006. PMC: 5462749. DOI: 10.1038/s41598-017-03418-0. View

20.

Silverman A, Nakata R, Shimada H, Sposto R, DeClerck Y . A galectin-3-dependent pathway upregulates interleukin-6 in the microenvironment of human neuroblastoma. Cancer Res. 2012; 72(9):2228-38. PMC: 3815584. DOI: 10.1158/0008-5472.CAN-11-2165. View