Spatial Sequestration of Activated-caspase 3 in Aggresomes Mediates Resistance of Neuroblastoma Cell to Bortezomib Treatment

Overview

Journal Sci Rep

Specialty Science

Date 2024 Feb 15

PMID 38355966

Authors

Kevin Berthenet

Eliezer Aimontche

Sara El Mrini

Johan Briere

Nathalie Pion

Isabelle Iacono

Stephanie Brejon

Karine Monier

Frederic Catez

Gabriel Ichim

Valerie Combaret

Hichem C Mertani

Jean-Jacques Diaz

Marie Alexandra Albaret

Affiliations

Soon will be listed here.

Abstract

Neuroblastoma (NB) is the most common pediatric tumor and is currently treated by several types of therapies including chemotherapies, such as bortezomib treatment. However, resistance to bortezomib is frequently observed by mechanisms that remain to be deciphered. Bortezomib treatment leads to caspase activation and aggresome formation. Using models of patients-derived NB cell lines with different levels of sensitivity to bortezomib, we show that the activated form of caspase 3 accumulates within aggresomes of NB resistant cells leading to an impairment of bortezomib-induced apoptosis and increased cell survival. Our findings unveil a new mechanism of resistance to chemotherapy based on an altered subcellular distribution of the executioner caspase 3. This mechanism could explain the resistance developed in NB patients treated with bortezomib, emphasizing the potential of drugs targeting aggresomes.

References

Takahashi M, Kitaura H, Kakita A, Kakihana T, Katsuragi Y, Nameta M . USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis. iScience. 2018; 9:433-450. PMC: 6249355. DOI: 10.1016/j.isci.2018.11.006. View

DAmours D, Sallmann F, Dixit V, Poirier G . Gain-of-function of poly(ADP-ribose) polymerase-1 upon cleavage by apoptotic proteases: implications for apoptosis. J Cell Sci. 2001; 114(Pt 20):3771-8. DOI: 10.1242/jcs.114.20.3771. View

Wang J, Jiang J, Chen H, Wang L, Guo H, Yang L . FDA-approved drug screen identifies proteasome as a synthetic lethal target in MYC-driven neuroblastoma. Oncogene. 2019; 38(41):6737-6751. DOI: 10.1038/s41388-019-0912-5. View

Mody R, Zhao L, Yanik G, Opipari V . Phase I study of bortezomib in combination with irinotecan in patients with relapsed/refractory high-risk neuroblastoma. Pediatr Blood Cancer. 2017; 64(11). DOI: 10.1002/pbc.26563. View

Walsh J, Logue S, Luthi A, Martin S . Caspase-1 promiscuity is counterbalanced by rapid inactivation of processed enzyme. J Biol Chem. 2011; 286(37):32513-24. PMC: 3173193. DOI: 10.1074/jbc.M111.225862. View

Nassar M, Samaha H, Ghabriel M, Yehia M, Taha H, Salem S . LC3A Silencing Hinders Aggresome Vimentin Cage Clearance in Primary Choroid Plexus Carcinoma. Sci Rep. 2017; 7(1):8022. PMC: 5556083. DOI: 10.1038/s41598-017-07403-5. View

Furfaro A, Piras S, Domenicotti C, Fenoglio D, De Luigi A, Salmona M . Role of Nrf2, HO-1 and GSH in Neuroblastoma Cell Resistance to Bortezomib. PLoS One. 2016; 11(3):e0152465. PMC: 4811586. DOI: 10.1371/journal.pone.0152465. View

Michaelis M, Fichtner I, Behrens D, Haider W, Rothweiler F, Mack A . Anti-cancer effects of bortezomib against chemoresistant neuroblastoma cell lines in vitro and in vivo. Int J Oncol. 2006; 28(2):439-46. View

Zafar A, Wang W, Liu G, Wang X, Xian W, McKeon F . Molecular targeting therapies for neuroblastoma: Progress and challenges. Med Res Rev. 2020; 41(2):961-1021. PMC: 7906923. DOI: 10.1002/med.21750. View

10.

Esiashvili N, Anderson C, Katzenstein H . Neuroblastoma. Curr Probl Cancer. 2010; 33(6):333-60. DOI: 10.1016/j.currproblcancer.2009.12.001. View

11.

Kristiansen M, Messenger M, Klohn P, Brandner S, Wadsworth J, Collinge J . Disease-related prion protein forms aggresomes in neuronal cells leading to caspase activation and apoptosis. J Biol Chem. 2005; 280(46):38851-61. DOI: 10.1074/jbc.M506600200. View

12.

Matthay K, Maris J, Schleiermacher G, Nakagawara A, Mackall C, Diller L . Neuroblastoma. Nat Rev Dis Primers. 2016; 2:16078. DOI: 10.1038/nrdp.2016.78. View

13.

Vegran F, Boidot R, Oudin C, Riedinger J, Lizard-Nacol S . [Implication of alternative splice transcripts of caspase-3 and survivin in chemoresistance]. Bull Cancer. 2005; 92(3):219-26. View

14.

Bolte S, Cordelieres F . A guided tour into subcellular colocalization analysis in light microscopy. J Microsc. 2007; 224(Pt 3):213-32. DOI: 10.1111/j.1365-2818.2006.01706.x. View

15.

Wong E, Tan J, Soong W, Hussein K, Nukina N, Dawson V . Autophagy-mediated clearance of aggresomes is not a universal phenomenon. Hum Mol Genet. 2008; 17(16):2570-82. PMC: 2722889. DOI: 10.1093/hmg/ddn157. View

16.

Tanaka M, Kim Y, Lee G, Junn E, Iwatsubo T, Mouradian M . Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem. 2003; 279(6):4625-31. DOI: 10.1074/jbc.M310994200. View

17.

Asadi M, Taghizadeh S, Kaviani E, Vakili O, Taheri-Anganeh M, Tahamtan M . Caspase-3: Structure, function, and biotechnological aspects. Biotechnol Appl Biochem. 2021; 69(4):1633-1645. DOI: 10.1002/bab.2233. View

18.

Chen D, Frezza M, Schmitt S, Kanwar J, Dou Q . Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets. 2011; 11(3):239-53. PMC: 3306611. DOI: 10.2174/156800911794519752. View

19.

Kawaguchi Y, Kovacs J, McLaurin A, Vance J, Ito A, Yao T . The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell. 2003; 115(6):727-38. DOI: 10.1016/s0092-8674(03)00939-5. View

20.

Mizushima N . Autophagy: process and function. Genes Dev. 2007; 21(22):2861-73. DOI: 10.1101/gad.1599207. View