Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Apr;78(8):3883-3906.
doi: 10.1007/s00018-021-03756-3. Epub 2021 Feb 18.

Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma

Sinan Xiong  1 , Wee-Joo Chng  2   3   4 , Jianbiao Zhou  5   6
Affiliations
Review

Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma

Sinan Xiong et al. Cell Mol Life Sci. 2021 Apr.

Abstract

Under physiological and pathological conditions, cells activate the unfolded protein response (UPR) to deal with the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. Multiple myeloma (MM) is a hematological malignancy arising from immunoglobulin-secreting plasma cells. MM cells are subject to continual ER stress and highly dependent on the UPR signaling activation due to overproduction of paraproteins. Mounting evidence suggests the close linkage between ER stress and oxidative stress, demonstrated by overlapping signaling pathways and inter-organelle communication pivotal to cell fate decision. Imbalance of intracellular homeostasis can lead to deranged control of cellular functions and engage apoptosis due to mutual activation between ER stress and reactive oxygen species generation through a self-perpetuating cycle. Here, we present accumulating evidence showing the interactive roles of redox homeostasis and proteostasis in MM pathogenesis and drug resistance, which would be helpful in elucidating the still underdefined molecular pathways linking ER stress and oxidative stress in MM. Lastly, we highlight future research directions in the development of anti-myeloma therapy, focusing particularly on targeting redox signaling and ER stress responses.

Keywords: Endoplasmic reticulum stress; Multiple myeloma; Oxidative stress; Reactive oxygen species; Unfolded protein response.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Signaling pathways associated with the UPR. To maintain ER homeostasis, accumulation of unfolded proteins that are bound by BiP in the ER activates three ER stress sensors, including IRE1, PERK and ATF6. However, chronic or excessive unresolved ER stress redirects the UPR pathways to trigger apoptosis. Dimerization and auto-phosphorylation of IRE1 induces its kinase and endoribonuclease activities, leading to phosphorylation of JNK and inhibitor of nuclear factor kappa B (IκB), unconventional splicing of XBP1 mRNA and RIDD. Similarly, dimerized PERK phosphorylates downstream targets eIF2α and NRF2 in the absence of BiP. On dissociation of BiP in the ER lumen, ATF6 translocates to the Golgi apparatus, where it undergoes cleavage by site-1 protease (S1P) and site-2 protease (S2P) to form the short-form ATF6 being redirected to the nucleus to mediate the expression of UPR downstream targets
Fig. 2
Fig. 2
Crosstalk between UPR and redox signaling. ER stress occurs when ER Ca2+ is exhausted or ROS are overproduced due to cumulative load of protein misfolding and high energy demand. This in turn leads to redox regulation of UPR pathways. Cysteine oxidation of IRE1 drives a pathway switch to activation of Nrf2 and antioxidant responses. Redox-sensitive PERK also activates PI3K-AKT pathway to mitigate oxidative stress, while AKT may facilitate Nrf2 activation. IRE1 and PERK are key components of MAM for maintaining ER-mitochondria juxtaposition and ROS-dependent mitochondria apoptosis
Fig. 3
Fig. 3
Differences between drug-sensitive and -resistant multiple myeloma cells. Anti-myeloma drug, such as proteasome inhibitor, induces apoptosis through multiple mechanisms, such as disruption of normal protein turnover by amino acid depletion, inhibition of ERAD, activation of UPR-mediated apoptosis signaling (e.g., CHOP, NOXA, DR5), induction of mitochondrial damage with increased Ca2+ transfer to the mitochondria at the MAM and reduction in antioxidant defense. Myeloma cells may acquire resistance through genetic mutations and/or transcriptional controls. This leads to downregulation of dependence on the UPR and upregulation of signaling pathways contributing to redox homeostasis, cellular survival and transition into quiescent state. NOXA/PMAIP1 phorbol-12-Myristate-13-Acetate-Induced Protein 1, DR5 death receptor 5
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Cid Ruzafa J, Merinopoulou E, Baggaley RF, Leighton P, Werther W, Felici D, Cox A. Patient population with multiple myeloma and transitions across different lines of therapy in the USA: an epidemiologic model. Pharmacoepidemiol Drug Saf. 2016;25(8):871–879. - PubMed
    1. Howlader N, Noone A, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis D, Chen H, Feuer E, Cronin K SEER Cancer Statistics Review, 1975–2017. National Cancer Institute. 2019. https://seer.cancer.gov/csr/1975_2017/. Accessed 12 April 2020
    1. Labbadia J, Morimoto RI. The biology of proteostasis in aging and disease. Annu Rev Biochem. 2015;84:435–464. - PMC - PubMed
    1. Loaiza S, Ferreira SA, Chinn TM, Kirby A, Tsolaki E, Dondi C, Parzych K, Strange AP, Bozec L, Bertazzo S. An engineered, quantifiable in vitro model for analysing the effect of proteostasis-targeting drugs on tissue physical properties. Biomaterials. 2018;183:102–113. - PMC - PubMed
    1. Saavedra-García P, Martini F, Auner HW. Proteasome inhibition in multiple myeloma: lessons for other cancers. Am J Physiol-Cell Physiol. 2020;318(3):C451–C462. - PubMed
-