Stew in its Own Juice: Protein Homeostasis Machinery Inhibition Reduces Cell Viability in Multiple Myeloma Cell Lines

Author(s): Mariana B. de Oliveira, Luiz F.G. Sanson, Angela I.P. Eugenio, Rebecca S.S. Barbosa-Dantas, Gisele W.B. Colleoni*.

Journal Name: Current Molecular Medicine

Volume 19 , Issue 2 , 2019

  Journal Home
Translate in Chinese
Submit Manuscript
Submit Proposal


Introduction: Multiple myeloma (MM) cells accumulate in the bone marrow and produce enormous quantities of immunoglobulins, causing endoplasmatic reticulum stress and activation of protein handling machinery, such as heat shock protein response, autophagy and unfolded protein response (UPR).

Methods: We evaluated cell lines viability after treatment with bortezomib (B) in combination with HSP70 (VER-15508) and autophagy (SBI-0206965) or UPR (STF- 083010) inhibitors.

Results: For RPMI-8226, after 72 hours of treatment with B+VER+STF or B+VER+SBI, we observed 15% of viable cells, but treatment with B alone was better (90% of cell death). For U266, treatment with B+VER+STF or with B+VER+SBI for 72 hours resulted in 20% of cell viability and both treatments were better than treatment with B alone (40% of cell death). After both triplet combinations, RPMI-8226 and U266 presented the overexpression of XBP-1 UPR protein, suggesting that it is acting as a compensatory mechanism, in an attempt of the cell to handle the otherwise lethal large amount of immunoglobulin overload.

Conclusion: Our in vitro results provide additional evidence that combinations of protein homeostasis inhibitors might be explored as treatment options for MM.

Keywords: Multiple myeloma, proteasome, HSP70, autophagy, UPR, UPS.

Rajkumar S, Kumar S. Multiple Myeloma: Diagnosis and Treatment. Mayo Clin Proc 2016; 91(1): 101-19.
Aronson LI, Davies FE. DangER: protein ovERload. Targeting protein degradation to treat myeloma. Haematologica 2012; 97(8): 1119-30.
Jego G, Hazoumé A, Seigneuric R, Garrido C. Targeting heat shock proteins in cancer. Cancer Lett 2013; 332(2): 275-85.
Zhang L, Fok JJL, Davies FE. Heat shock proteins in multiple myeloma. Oncotarget 2014; 5(5): 1132-45.
Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004; 6(4): 463-77.
Benbrook DM, Long A. Integration of autophagy, proteasomal degradation, unfolded protein response and apoptosis. Exp Oncol 2012; 34: 286-97.
Jung CH, Jun CB, Ro SH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 2009; 20(7): 1992-2003.
Matsunaga K, Saitoh T, Tabata K, et al. Two Beclin 1- binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 2009; 11(4): 385-96.
Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 2003; 23(21): 7448-59.
Hu MC, Gong HY, Lin GH, et al. XBP-1, a key regulator of unfolded protein response, activates transcription of IGF1 and Akt phosphorylation in zebrafish embryonic cell line. Biochem Biophys Res Commun 2007; 359(3): 778-83.
Adams J. Proteasome inhibition in cancer: Development of PS-341. Semin Oncol 2001; 28: 613-9.
Karin M, Cao Y, Greten FR, Li ZW. NF-kappa in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2002. 2:301-10. 15
Massey AJ, Williamson DS, Browne H, et al. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol 2010; 66(3): 535-45.
Zhang L, Fok JJL, Mirabella F, et al. HSP70 inhibition induces myeloma cell death via the intracellular accumulation of immunoglobulin and the generation of proteotoxic estress. Cancer Lett 2013; 339(1): 49-59.
Bailey CK, Budina-Kolomets A, Murphy ME, Nefedova Y. Efficacy of the HSP70 inhibitor PET-16 in multiple myeloma. Cancer Biol Ther 2015; 16(9): 1422-6.
Eugenio AIP, Fook-Alves VL, Oliveira MB, Fernando RC, Zanatta DB, Strauss BE, et al. . Proteasome and heat shock protein 70 (HSP70) inhibitors as therapeutic alternative in multiple myeloma. Oncotarget 2017. published online
Egan DF, Chun MG, Vamos M, et al. Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates. Mol Cell 2015; 59(2): 285-97.
Papandreou I, Denko NC, Olson M, et al. Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma. Blood 2011; 117(4): 1311-4.
de Oliveira MB, Fook-Alves VL, Eugenio AIP. etal. Anti-myeloma effects of ruxolitinib combined with bortezomib and lenalidomide: A rationale for JAK/STAT pathway inhibition in myeloma patients. Cancer Lett 2017; 403: 206-15.
Park J, Bae E, Lee C, et al. Establishment and characterization of bortezomib-resistant U266 cell line: Constitutive activation of NF-κB-mediated cell signals and/or alterations of ubiquitylation-related genes reduce bortezomib-induced apoptosis. BMB Rep 2014; 47(5): 274-9.
Fernando R, Carvalho F, Mazzotti D, et al. Multiple myeloma cell lines and primary tumors proteoma: protein biosynthesis and Immune system as potential therapeutic targets. Genes & Cancer [Internet] 2015; 6: 462-71.
Gene Cards® The Human Gene Database. Available at Access in: 14 November . 2017.
Walter P, and Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011; 3(34): 1081-6.
Urra H, Dufey E, Avril T, Chevet E, Hetz C. Endoplasmatic reticulum stress and the hallmarks of cancer. Trends Cancer 2016; 2(5): 252-62.
Li M, Wang J, Jing J, et al. Synergistic promotion of breast cancer cells by targeting molecular chaperone GRP78 and heat shock protein 70. J Cell Mol Med 2009; 13(11-12): 4540-50.
Deegan S, Saveljeva S, Gorman AM, Samali A. Stress-induced self-cannibalism: on the regulation of autophagy by endoplasmic reticulum stress. Cell Mol Life Sci 2013; 70: 2425-41.
Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta 2013; 1833: 3460-70.
Lee AH, Iwakoshi NN, Anderson KC, Glimcher LH. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci USA 2003; 100(17): 9946-51.
Kumar SK, Callander NS, Alsina M, et al. Multiple myeloma, version 3. 2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2017; 15: 230-69.
Bulatov E, Zagidullin A, Valiullina A, Savarona R, Rizvanov A. Small molecule modulators of RING-Type E3 ligases: MDM and Cullin Families as targets. Front Pharmacol 2018; 9: 450.
Hoang B, Benavides A, Shi Y, Frost P, Lichtenstein A. Effect of autophagy on multiple myeloma cell viability. Mol Cancer Ther 2009; 8(7): 1974-84.
Mimura N, Fulciniti M, Gorgun G, et al. Blockage of XBP1splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma. Blood 2012; 119: 5772-81.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [112 - 119]
Pages: 8
DOI: 10.2174/1566524019666190305134441
Price: $58

Article Metrics

PDF: 32
PRC: 1