The Role of Chaperone-Mediated Autophagy in Bortezomib Resistant Multiple Myeloma

Nicholas Nikesitch; Patricia Rebeiro; Lye Lin Ho; Srinivasa Pothula; Xin Maggie Wang; Tiffany Khong; Hazel Quek; Andrew Spencer; Cheok Soon Lee; Tara L. Roberts; Silvia C. W. Ling

doi:10.3390/cells10123464

journal article Open Access Dec 08, 2021

The Role of Chaperone-Mediated Autophagy in Bortezomib Resistant Multiple Myeloma

Nicholas Nikesitch Patricia Rebeiro Lye Lin Ho Srinivasa Pothula Xin Maggie Wang Tiffany Khong

Hazel Quek

Andrew Spencer

Cheok Soon Lee Tara L. Roberts

Silvia C. W. Ling

Cells Vol. 10 No. 12 pp. 3464 · MDPI AG

View at Publisher Save 10.3390/cells10123464

Abstract

Background: Multiple myeloma (MM) remains incurable despite high-dose chemotherapy, autologous stem cell transplants and novel agents. Even with the improved survival of MM patients treated with novel agents, including bortezomib (Bz), the therapeutic options in relapsed/refractory MM remain limited. The majority of MM patients eventually develop resistance to Bz, although the mechanisms of the resistance are poorly understood. Methods: Lysosomal associated membrane protein 2A (LAMP2A) mRNA and protein expression levels were assessed in ex vivo patient samples and a Bz-resistant MM cell line model by in real-rime PCR, western blotting and immunohistochemistry. In vitro modelling of chaperone-mediated autophagy (CMA) activity in response to ER stress were assessed by western blotting and confocal microscopy. The effects of CMA inhibition on MM cell viability and Bz sensitivity in MM cells were assessed by Annexin V/7AAD apoptosis assays using flow cytometry. Results: In this study, there is evidence that CMA, a chaperone-mediated protein degradation pathway, is upregulated in Bz-resistant MM and the inhibition of CMA sensitises resistant cells to Bz. The protein levels of LAMP2A, the rate-limiting factor of the CMA pathway, are significantly increased in MM patients resistant to Bz and within our Bz-resistant cell line model. Bz-resistant cell lines also possessed higher basal CMA activity than the Bz-sensitive parent cell line. In MM cell lines, CMA activity was upregulated in response to ER stress induced by Bz. The inhibition of CMA sensitises Bz-resistant cells to Bz and the combination of CMA inhibition and Bz in vitro had a more cytotoxic effect on myeloma cells than Bz alone. Conclusion: In summary, the upregulation of CMA is a potential mechanism of resistance to Bz and a novel target to overcome Bz-resistant MM.

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References

38

[1]

Manier "Genomic complexity of multiple myeloma and its clinical implications" Nat. Rev. Clin. Oncol. (2017) 10.1038/nrclinonc.2016.122

[2]

Nikesitch "Molecular mechanisms in multiple myeloma drug resistance" J. Clin. Pathol. (2016) 10.1136/jclinpath-2015-203414

[3]

Nikesitch "Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance" Clin. Transl. Immunol. (2018) 10.1002/cti2.1007

[4]

Chen "Bortezomib as the first proteasome inhibitor anticancer drug: Current status and future perspectives" Curr. Cancer Drug Targets (2011) 10.2174/156800911794519752

[5]

Ling "Response of myeloma to the proteasome inhibitor bortezomib is correlated with the unfolded protein response regulator XBP-1" Haematologica (2012) 10.3324/haematol.2011.043331

[6]

Nikesitch "Predicting the response of multiple myeloma to the proteasome inhibitor Bortezomib by evaluation of the unfolded protein response" Blood Cancer J. (2016) 10.1038/bcj.2016.40

[7]

Dice "Chaperone-mediated autophagy" Autophagy (2007) 10.4161/auto.4144

[8]

Kon "Chaperone-mediated autophagy in health and disease" FEBS Lett. (2010) 10.1016/j.febslet.2009.12.025

[9]

Kon "Chaperone-mediated autophagy is required for tumor growth" Sci. Transl. Med. (2011) 10.1126/scitranslmed.3003182

[10]

Ding "Lamp2a is required for tumor growth and promotes tumor recurrence of hepatocellular carcinoma" Int. J. Oncol. (2016) 10.3892/ijo.2016.3754

[11]

Saha "LAMP2A overexpression in breast tumors promotes cancer cell survival via chaperone-mediated autophagy" Autophagy (2012) 10.4161/auto.21654

[12]

Acetylation Targets the M2 Isoform of Pyruvate Kinase for Degradation through Chaperone-Mediated Autophagy and Promotes Tumor Growth

Lei Lv, Dong Li, Di Zhao et al.

Molecular Cell 2011 10.1016/j.molcel.2011.04.025

[13]

Kaushik "Autophagy as a cell-repair mechanism: Activation of chaperone-mediated autophagy during oxidative stress" Mol. Asp. Med. (2006) 10.1016/j.mam.2006.08.007

[14]

Wang "Macroautophagy and chaperone-mediated autophagy are required for hepatocyte resistance to oxidant stress" Hepatology (2010) 10.1002/hep.23645

[15]

Tasset "Role of chaperone-mediated autophagy in metabolism" FEBS J. (2016) 10.1111/febs.13677

[16]

Rajkumar "Consensus recommendations for the uniform reporting of clinical trials: Report of the International Myeloma Workshop Consensus Panel 1" Blood (2011) 10.1182/blood-2010-10-299487

[17]

Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method

Kenneth J. Livak, Thomas D. Schmittgen

Methods 2001 10.1006/meth.2001.1262

[18]

Kaushik "Constitutive activation of chaperone-mediated autophagy in cells with impaired macroautophagy" Mol. Biol. Cell (2008) 10.1091/mbc.e07-11-1155

[19]

Bolte "A guided tour into subcellular colocalization analysis in light microscopy" J. Microsc.-Oxf. (2006) 10.1111/j.1365-2818.2006.01706.x

[20]

Niewerth "Molecular basis of resistance to proteasome inhibitors in hematological malignancies" Drug Resist. Updat. (2015) 10.1016/j.drup.2014.12.001

[21]

Soriano "Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes, in particular in redox and energy metabolism" Leukemia (2016) 10.1038/leu.2016.102

[22]

Mechanisms of chaperone-mediated autophagy

Amy E. Majeski, J. Fred Dice

The International Journal of Biochemistry & Ce... 2004 10.1016/j.biocel.2004.02.013

[23]

Ikeda "The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo" Clin. Cancer Res. (2009) 10.1158/1078-0432.ccr-08-2867

[24]

Lukesh "A potent, versatile disulfide-reducing agent from aspartic acid" J. Am. Chem. Soc. (2012) 10.1021/ja211931f

[25]

Arias "Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy" Mol. Cell (2015) 10.1016/j.molcel.2015.05.030

[26]

Bandyopadhyay "Identification of regulators of chaperone-mediated autophagy" Mol. Cell (2010) 10.1016/j.molcel.2010.08.004

[27]

Schlag "Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma" N. Engl. J. Med. (2008) 10.1056/nejmoa0801479

[28]

Kaushik "Inhibitory effect of dietary lipids on chaperone-mediated autophagy" Proc. Natl. Acad. Sci. USA (2012)

[29]

Mony "A lysosome-centered view of nutrient homeostasis" Autophagy (2016) 10.1080/15548627.2016.1147671

[30]

Zhou "Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging" Aging (2017) 10.18632/aging.101181

[31]

Cuervo "IkappaB is a substrate for a selective pathway of lysosomal proteolysis" Mol. Biol. Cell (1998) 10.1091/mbc.9.8.1995

[32]

Zhou "Chaperone-mediated autophagy regulates proliferation by targeting RND3 in gastric cancer" Autophagy (2016) 10.1080/15548627.2015.1136770

[33]

Hideshima "NF-kappa B as a therapeutic target in multiple myeloma" J. Biol. Chem. (2002) 10.1074/jbc.m200360200

[34]

Annunziata "Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma" Cancer Cell (2007) 10.1016/j.ccr.2007.07.004

[35]

Li "NF-kappaB in the pathogenesis and treatment of multiple myeloma" Curr. Opin. Hematol. (2008) 10.1097/moh.0b013e328302c7f4

[36]

Demchenko "Classical and/or alternative NF-kappaB pathway activation in multiple myeloma" Blood (2010) 10.1182/blood-2009-09-243535

[37]

Erdmann "Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma" Cancer Cell (2013) 10.1016/j.ccr.2013.08.009

[38]

High XBP1 expression is a marker of better outcome in multiple myeloma patients treated with bortezomib

M. Gambella, A. Rocci, R. Passera et al.

Haematologica 2014 10.3324/haematol.2013.090142

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Details

Published: Dec 08, 2021
Vol/Issue: 10(12)
Pages: 3464
License: View

Authors

N

Nicholas Nikesitch

School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; Ingham Institute of Applied Medical Research, Liverpool, NSW 2170, Australia; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada

P

Patricia Rebeiro

Ingham Institute of Applied Medical Research, Liverpool, NSW 2170, Australia; Department of Haematology, Liverpool Hospital, Liverpool, NSW 2170, Australia; School of Medicine, University of New South Wales, Kensington, NSW 2033, Australia; NSW Health Pathology, Liverpool Hospital, Pathology Building, Liverpool, NSW 2170, Australia

L

Lye Lin Ho

Department of Haematology, Liverpool Hospital, Liverpool, NSW 2170, Australia; NSW Health Pathology, Liverpool Hospital, Pathology Building, Liverpool, NSW 2170, Australia

S

Srinivasa Pothula

Ingham Institute of Applied Medical Research, Liverpool, NSW 2170, Australia; School of Medicine, University of New South Wales, Kensington, NSW 2033, Australia

X

Xin Maggie Wang

Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia

T

Tiffany Khong

Malignant Haematology & Stem Cell Transplantation Service, Alfred Hospital, Melbourne, VIC 3004, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia

H

Hazel Quek

QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia

A

Andrew Spencer

Malignant Haematology & Stem Cell Transplantation Service, Alfred Hospital, Melbourne, VIC 3004, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia

C

Cheok Soon Lee

School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; Ingham Institute of Applied Medical Research, Liverpool, NSW 2170, Australia; School of Medicine, University of New South Wales, Kensington, NSW 2033, Australia; NSW Health Pathology, Liverpool Hospital, Pathology Building, Liverpool, NSW 2170, Australia; Department of Anatomical Pathology, Liverpool Hospital, Sydney, NSW 2170, Australia

T

Tara L. Roberts

School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; Ingham Institute of Applied Medical Research, Liverpool, NSW 2170, Australia; School of Medicine, University of New South Wales, Kensington, NSW 2033, Australia; Faculty of Medicine, University of Queensland Centre for Clinical Research, Herston, QLD 4006, Australia

S

Silvia C. W. Ling

School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; Ingham Institute of Applied Medical Research, Liverpool, NSW 2170, Australia; Department of Haematology, Liverpool Hospital, Liverpool, NSW 2170, Australia; School of Medicine, University of New South Wales, Kensington, NSW 2033, Australia; NSW Health Pathology, Liverpool Hospital, Pathology Building, Liverpool, NSW 2170, Australia

Cite This Article

Nicholas Nikesitch, Patricia Rebeiro, Lye Lin Ho, et al. (2021). The Role of Chaperone-Mediated Autophagy in Bortezomib Resistant Multiple Myeloma. Cells, 10(12), 3464. https://doi.org/10.3390/cells10123464

The Role of Chaperone-Mediated Autophagy in Bortezomib Resistant Multiple Myeloma

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