Prenyltransferases Regulate CD20 Protein Levels and Influence Anti-CD20 Monoclonal Antibody-mediated Activation of Complement-dependent Cytotoxicity

Winiarska, Magdalena; Nowis, Dominika; Bil, Jacek; Głodkowska-Mrówka, Eliza; Muchowicz, Angelika; Wańczyk, Małgorzata; Bojarczuk, Kamil; Dwojak, Michal; Firczuk, Małgorzata; Wilczek, Ewa; Wachowska, Malgorzata; Roszczenko, Katarzyna; Miączyńska, Marta; Chlebowska, Justyna; Basak, Grzegorz W.; Gołąb, Jakub

doi:10.1074/jbc.m112.374751

Cited by 20 publications

(16 citation statements)

References 37 publications

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“…Previous reports demonstrated that GEM also activated NF‐ k B in pancreatic cancer cells . The CD20 gene promoter contains binding sites to Sp1, NF‐ k B, Oct and PU.1 . Based on these findings, we presume that GEM‐activated NF‐ k B binds to the CD20 promoter to induce CD20 transcriptional activation.…”

Section: Discussionsupporting

confidence: 56%

“…Some therapeutic agents, such as farnesyltransferase inhibitors, bryostatin‐1, histone deacetylase inhibitors and some cytokines, can enhance CD20 expression in lymphoma, and upregulation of CD20 expression on B cell lymphoma cells increases the cytotoxic activity of rituximab . In the present study, we demonstrate that gemcitabine (GEM), which is conventionally used for DLBCL treatment, augments CD20 expression on DLBCL cells.…”

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confidence: 50%

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Gemcitabine enhances rituximab‐mediated complement‐dependent cytotoxicity to B cell lymphoma by CD20 upregulation

et al. 2016

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Although rituximab, a chimeric monoclonal antibody that specifically binds to CD20, has significantly improved the prognosis for diffuse large B cell lymphoma (DLBCL), one‐third of DLBCL patients demonstrate resistance to rituximab or relapse after rituximab treatment. Thus, a novel approach to rituximab‐based treatment is likely to be required to improve the efficacy of DLBCL treatment. As complement dependent cytotoxicity (CDC) is a key mechanism mediating rituximab's tumoricidal activity, rituximab binding to CD20 on tumor cells is a critical factor for effective rituximab‐based treatments against DLBCL. We found that gemcitabine (GEM), but not lenalidomide (LEN) or azacitidine (AZA), can upregulate CD20 expression in TK and KML‐1 cells, two human DLBCL cell lines. Treatment of TK and KML‐1 cells with GEM enhanced CD20 expression at both the mRNA and protein levels. CD20 upregulation by GEM treatment was accompanied by increased rituximab binding to CD20. In TK cells, GEM treatment synergistically increased rituximab‐mediated CDC activity in a dose‐dependent manner. In KML cells, GEM treatment also induced upregulation of complement regulatory proteins, possibly leading to resistance to CDC. Treatment with LEN, a drug that did not upregulate CD20, did not enhance rituximab‐mediated CDC activity. GEM treatment activated nuclear factor‐kappa B (NF‐kB) signaling in these cells. Furthermore, a specific inhibitor to NF‐kB suppressed GEM‐induced CD20 upregulation, indicating that GEM‐induced NF‐kB activation is closely associated with CD20 upregulation. These results suggest that when used in combination, GEM might enhance the antitumor efficacy of rituximab against DLBCL due to its unique ability to upregulate CD20.

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Section: Discussionsupporting

confidence: 56%

supporting

confidence: 50%

Gemcitabine enhances rituximab‐mediated complement‐dependent cytotoxicity to B cell lymphoma by CD20 upregulation

et al. 2016

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“…Furthermore, CD20 expression is highly variable and rather low on the cells of chronic lymphocytic leukemia (CLL) when compared to other B-cell malignancies or healthy B cells [3]. Notably, some experimental approaches to pharmacologically modulate CD20 expression levels were proposed, nevertheless, none of the strategies has ever been transferred into the clinical use [4,5]. So far, it is impossible to predict CD20 expression changes, as the precise molecular mechanisms of CD20 regulation and its biological function remain largely elusive.…”

Section: Introductionmentioning

confidence: 99%

CD20 is dispensable for B-cell receptor signaling but is required for proper actin polymerization, adhesion and migration of malignant B cells

et al. 2020

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Surface protein CD20 serves as the critical target of immunotherapy in various B-cell malignancies for decades, however its biological function and regulation remain largely elusive. Better understanding of CD20 function may help to design improved rational therapies to prevent development of resistance. Using CRISPR/Cas9 technique, we have abrogated CD20 expression in five different malignant B-cell lines. We show that CD20 deletion has no effect upon B-cell receptor signaling or calcium flux. Also B-cell survival and proliferation is unaffected in the absence of CD20. On the contrary, we found a strong defect in actin cytoskeleton polymerization and, consequently, defective cell adhesion and migration in response to homeostatic chemokines SDF1α, CCL19 and CCL21. Mechanistically, we could identify a reduction in chemokine-triggered PYK2 activation, a calcium-activated signaling protein involved in activation of MAP kinases and cytoskeleton regulation. These cellular defects in consequence result in a severely disturbed homing of B cells in vivo.

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“…Lipid rafts are specialized microdomains of the plasma membrane that are enriched in sphingolipid and cholesterol, and play an important role in the initiation of many anticancer drug-induced signaling pathways and toxicological effects. Anticancer drugs are able to suppress cell growth and induce apoptosis of tumor cells through disrupting lipid raft integrity [32,47]. The redistribution of CD-20 may result in lipid raft disruption, activate or deactivate raft-associated proteins, such as death receptors and protein kinases in apoptotic pathway which are correlated with efficiency of complementdependent cytotoxicity and antibody-dependent cellmediated cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Targeting cholesterol synthesis increases chemoimmuno-sensitivity in chronic lymphocytic leukemia cells

Huang¹

2016

J Glycomics Lipidomics

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Background: Cholesterol plays an important role in cancer development, drug resistance and chemoimmuno-sensitivity. Statins, cholesterol lowering drugs, can induce apoptosis, but also negatively interfere with CD-20 and rituximab-mediated activity. Our goal is to identify the alternative targets that could reduce cholesterol levels but do not interfere with CD-20 in chemo immunotherapy of chronic lymphocytic leukemia (CLL).

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Prenyltransferases Regulate CD20 Protein Levels and Influence Anti-CD20 Monoclonal Antibody-mediated Activation of Complement-dependent Cytotoxicity

Cited by 20 publications

References 37 publications

Gemcitabine enhances rituximab‐mediated complement‐dependent cytotoxicity to B cell lymphoma by CD20 upregulation

Gemcitabine enhances rituximab‐mediated complement‐dependent cytotoxicity to B cell lymphoma by CD20 upregulation

CD20 is dispensable for B-cell receptor signaling but is required for proper actin polymerization, adhesion and migration of malignant B cells

Targeting cholesterol synthesis increases chemoimmuno-sensitivity in chronic lymphocytic leukemia cells

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