Antiapoptotic properties of MALT1 protease are associated with redox homeostasis in ABC‐DLBCL cells

Zhu, Leqing; Tang, Fen; Lei, Zhiwei; Guo, Chengbin; Song, Yueqi; Huang, Junqing; Xia, Xichun

doi:10.1002/mc.23122

Cited by 6 publications

(3 citation statements)

References 44 publications

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“…Many studies have demonstrated that ABC family genes play important roles in the maintaining cellular environment [ 26 , 27 ], cholesterol metabolism [ 9 , 10 , 28–31 ], disease occurrence [ 32–34 ], and tumor resistance [ 35 , 36 ]. ABC transporter genes could promote drug efflux and enhance chemical resistance of cancer cells [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and prognostic value of ABC transporter family member ABCG1 gene in clear cell renal cell carcinoma

et al. 2021

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As the most common histologic subtype of renal cancer, clear cell renal cell carcinoma (ccRCC) poses a serious threat to public health. However, there are no specific molecular-targeted drugs for ccRCC at present. Human ATP-binding cassette (ABC) transporter family plays an important role in homeostasis maintenance. This study aimed to evaluate the potential diagnostic value of ABC genes in ccRCC. A total of 952 samples of ccRCC patients (707) and controls (245) from three different datasets were included for analysis. Receiver operating characteristic analysis and t-test were used to analyze the differential expression of ABC genes in ccRCC patients and control samples at mRNA level during screening and validations. The Cancer Genome Atlas (TCGA-ccRCC) dataset was utilized to investigate the correlation between ABC genes expression and prognostic value in ccRCC. We then investigated the interactions between ABCG1 and proteins in the Comparative Toxicogenomics Database (CTD). Finally, we found that ATP-binding cassette transporter G member 1 ( ABCG1 ) was over-expressed in ccRCC patients compared with healthy samples at mRNA level. Cox regression analysis and Kaplan–Meier analysis showed that ccRCC patients with high ABCG1 expression had better overall survival (OS) than those patients with low expression (hazard ratio (HR) = 0.662, p = 0.007). This study demonstrated that ABCG1 is a potential diagnostic and prognostic biomarker in ccRCC and discussed the molecular mechanisms underlying the relationship between ccRCC and ABCG1 , which might provide guidance for better management and treatment of ccRCC in the future.

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Section: Discussionmentioning

confidence: 99%

Diagnostic and prognostic value of ABC transporter family member ABCG1 gene in clear cell renal cell carcinoma

et al. 2021

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“…Indeed, MALT1 has been implicated in glutamine metabolism and redox homeostasis in lymphocytes. 30 Reciprocally, genes whose knockdown increased sensitivity to MI-2 (n 5 328; RIGER score , 21.0 and P , .15) were used to explore MALT1i sensitizers (Figure 2B; supplemental Figure 2B; supplemental Table 4). "Metabolic pathways" (including "Amino acid biosynthesis," "Purine metabolism," and "Glycolysis"; P 5 1.19e-09) were depleted from MI-2-resistant cells, pointing to the dependency of ABC-DLBCL on anabolic pathways and high glucose usage.…”

Section: Malt1i Is Modulated Through Specific Pathways In Abc-dlbcl C...mentioning

confidence: 99%

Identification of MALT1 feedback mechanisms enables rational design of potent antilymphoma regimens for ABC-DLBCL

Fontán

Goldstein

Casalena

et al. 2021

Blood

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MALT1 inhibitors are promising therapeutic agents for B-cell lymphomas that are dependent on constitutive or aberrant signaling pathways. However, a potential limitation for signal transduction–targeted therapies is the occurrence of feedback mechanisms that enable escape from the full impact of such drugs. Here, we used a functional genomics screen in activated B-cell–like (ABC) diffuse large B-cell lymphoma (DLBCL) cells treated with a small molecule irreversible inhibitor of MALT1 to identify genes that might confer resistance or enhance the activity of MALT1 inhibition (MALT1i). We find that loss of B-cell receptor (BCR)- and phosphatidylinositol 3-kinase (PI3K)-activating proteins enhanced sensitivity, whereas loss of negative regulators of these pathways (eg, TRAF2, TNFAIP3) promoted resistance. These findings were validated by knockdown of individual genes and a combinatorial drug screen focused on BCR and PI3K pathway–targeting drugs. Among these, the most potent combinatorial effect was observed with PI3Kδ inhibitors against ABC-DLBCLs in vitro and in vivo, but that led to an adaptive increase in phosphorylated S6 and eventual disease progression. Along these lines, MALT1i promoted increased MTORC1 activity and phosphorylation of S6K1-T389 and S6-S235/6, an effect that was only partially blocked by PI3Kδ inhibition in vitro and in vivo. In contrast, simultaneous inhibition of MALT1 and MTORC1 prevented S6 phosphorylation, yielded potent activity against DLBCL cell lines and primary patient specimens, and resulted in more profound tumor regression and significantly improved survival of ABC-DLBCLs in vivo compared with PI3K inhibitors. These findings provide a basis for maximal therapeutic impact of MALT1 inhibitors in the clinic, by disrupting feedback mechanisms that might otherwise limit their efficacy.

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“…To date, reports suggest that pharmacological inhibition of MALT1 leads to apoptosis in various cell types [18][19][20][21]. Jiang et al recently demonstrated that MI-2 inhibition of MALT1 reduces I/Rinduced myocardial ferroptosis through the enhancement of the nuclear factor erythroid-2/solute carrier family 7 member 11 (Nrf2/ SLC7A11) pathway [17], suggesting a role for MALT1 in the occurrence of ferroptosis.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) induces ferroptosis in vascular smooth muscle cells

Yan,

Belke,

Gui

et al. 2023

Cell Death Discov.

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MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) is a human paracaspase protein with proteolytic activity via its caspase-like domain. The pharmacological inhibition of MALT1 by MI-2, a specific chemical inhibitor, diminishes the response of endothelial cells to inflammatory stimuli. However, it is largely unknown how MALT1 regulates the functions of vascular smooth muscle cells (SMCs). This study aims to investigate the impact of MALT1 inhibition by MI-2 on the functions of vascular SMCs, both in vitro and in vivo. MI-2 treatment led to concentration- and time-dependent cell death of cultured aortic SMCs, which was rescued by the iron chelator deferoxamine (DFO) or ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, but not by inhibitors of apoptosis (Z-VAD-fmk), pyroptosis (Z-YVAD-fmk), or necrosis (Necrostatin-1, Nec-1). MI-2 treatment downregulated the expression of glutathione peroxidase 4 (GPX4) and ferritin heavy polypeptide 1 (FTH1), which was prevented by pre-treatment with DFO or Fer-1. MI-2 treatment also activated autophagy, which was inhibited by Atg7 deficiency or bafilomycin A1 preventing MI-2-induced ferroptosis. MI-2 treatment reduced the cleavage of cylindromatosis (CYLD), a specific substrate of MALT1. Notably, MI-2 treatment led to a rapid loss of contractility in mouse aortas, which was prevented by co-incubation with Fer-1. Moreover, local application of MI-2 significantly reduced carotid neointima lesions and atherosclerosis in C57BL/6J mice and apolipoprotein-E knockout (ApoE−/−) mice, respectively, which were both ameliorated by co-treatment with Fer-1. In conclusion, the present study demonstrated that MALT1 inhibition induces ferroptosis of vascular SMCs, likely contributing to its amelioration of proliferative vascular diseases.

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Antiapoptotic properties of MALT1 protease are associated with redox homeostasis in ABC‐DLBCL cells

Cited by 6 publications

References 44 publications

Diagnostic and prognostic value of ABC transporter family member ABCG1 gene in clear cell renal cell carcinoma

Diagnostic and prognostic value of ABC transporter family member ABCG1 gene in clear cell renal cell carcinoma

Identification of MALT1 feedback mechanisms enables rational design of potent antilymphoma regimens for ABC-DLBCL

Pharmacological inhibition of MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) induces ferroptosis in vascular smooth muscle cells

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