Overexpression of the pp32r1 (ANP32C) oncogene or its functional mutant pp32r1Y140H confers enhanced resistance to FTY720 (Finguimod)

Buddaseth, Salma; Göttmann, Wiebke; Blasczyk, Rainer; Huyton, Trevor

doi:10.4161/cbt.27307

Cited by 11 publications

(10 citation statements)

References 39 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These include transcriptional and post-transcriptional regulation, control by post-translational modifications and ubiquitin-mediated proteasomal degradation, as well as temporal and sub-cellular control2829. Moreover, PP2A enzymatic activity is regulated by endogenous inhibitory proteins (including ANP32A29, ANP32C30, I2PP2A/SET31, and CIP2A32) and modulated by the nature and identity of the PP2A regulatory subunits. Whether interaction of PADs with PP2A-inhibitory interactors (such as reported for FTY720 and I2PP2A/SET in the regulation of tumor suppression7) is responsible for their beneficial actions in respiratory inflammation is unknown at present and warrants further in-depth investigation.…”

Section: Discussionmentioning

confidence: 99%

The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

Rahman

Prünte

Lebender

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Protein phosphatase 2A (PP2A) activity can be enhanced pharmacologically by PP2A-activating drugs (PADs). The sphingosine analog FTY720 is the best known PAD and we have shown that FTY720 represses production of pro-inflammatory cytokines responsible for respiratory disease pathogenesis. Whether its phosphorylated form, FTY720-P, also enhances PP2A activity independently of the sphingosine 1-phosphate (S1P) pathway was unknown. Herein, we show that FTY720-P enhances TNF-induced PP2A phosphatase activity and significantly represses TNF-induced interleukin 6 (IL-6) and IL-8 mRNA expression and protein secretion from A549 lung epithelial cells. Comparing FTY720 and FTY720-P with S1P, we show that unlike S1P, the sphingosine analogs do not induce cytokine production on their own. In fact, FTY720 and FTY720-P significantly repress S1P-induced IL-6 and IL-8 production. We then examined their impact on expression of cyclooxygenase 2 (COX-2) and resultant prostaglandin E2 (PGE2) production. S1P did not increase production of this pro-inflammatory enzyme because COX-2 mRNA gene expression is NF-κB-dependent, and unlike TNF, S1P did not activate NF-κB. However, TNF-induced COX-2 mRNA expression and PGE2 secretion is repressed by FTY720 and FTY720-P. Hence, FTY720-P enhances PP2A activity and that PADs can repress production of pro-inflammatory cytokines and enzymes in A549 lung epithelial cells in a manner devoid of S1P agonism.

show abstract

Section: Discussionmentioning

confidence: 99%

The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

Rahman

Prünte

Lebender

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…This approach can be helped by the large scale sequencing studies currently undertaken in several countries with the aim of defining specific cancer mutations/genetic aberrations in large groups of patients. For example it was shown that cancer cells overexpressing pp32r1 or a pp32r1Y140H functional mutant in the ANP32C oncogene that is overexpressed in breast, prostate and pancreatic tumours, may demonstrate enhanced resistance to FTY720 treatment through conserved residue F136, likely to be a key determinant of the FTY720 binding site [ 247 ]. However it is not known whether this mutation is present in large human populations.…”

Section: Expert Commentarymentioning

confidence: 99%

The emerging role of FTY720 (Fingolimod) in cancer treatment

et al. 2016

View full text Add to dashboard Cite

FTY720 (Fingolimod) is a clinically approved immunomodulating therapy for multiple sclerosis that sequesters T-cells to lymph nodes through functional antagonism of sphingosine-1-phosphate 1 receptor. FTY720 also demonstrates a proven efficacy in multiple in vitro and in vivo cancer models, suggesting a potential therapeutic role in cancer patients. A potential anticancer mechanism of FTY720 is through the inhibition of sphingosine kinase 1, a proto-oncogene with in vitro and clinical cancer association. In addition, FTY720's anticancer properties may be attributable to actions on several other molecular targets. This study focuses on reviewing the emerging evidence regarding the anticancer properties and molecular targets of FTY720. While the clinical transition of FTY720 is currently limited by its immune suppression effects, studies aiming at FTY720 delivery and release together with identifying its key synergetic combinations and relevant patient subsets may lead to its rapid introduction into the clinic.

show abstract

“…Here we examine the evidence for ANP32C , also known as pp32r1, which is the most frequently described of these intronless sequences in the literature 30 – 35 . This open-reading frame has physiological effects when ectopically expressed 17 , 30 – 33 but doubts surround its endogenous expression. On a genomic level, ANP32C is not conserved from rodent to human.…”

Section: The Intronless Anp32 Loci: Expressed and Functional?mentioning

confidence: 99%

Cracking the ANP32 whips: Important functions, unequal requirement, and hints at disease implications

Reilly

Hamiche

et al. 2014

BioEssays

View full text Add to dashboard Cite

The acidic (leucine-rich) nuclear phosphoprotein 32 kDa (ANP32) family is composed of small, evolutionarily conserved proteins characterized by an N-terminal leucine-rich repeat domain and a C-terminal low-complexity acidic region. The mammalian family members (ANP32A, ANP32B, and ANP32E) are ascribed physiologically diverse functions including chromatin modification and remodelling, apoptotic caspase modulation, protein phosphatase inhibition, as well as regulation of intracellular transport. In addition to reviewing the widespread literature on the topic, we present a concept of the ANP32s as having a whip-like structure. We also present hypotheses that ANP32C and other intronless sequences should not currently be considered bona fide family members, that their disparate necessity in development may be due to compensatory mechanisms, that their contrasting roles in cancer are likely context-dependent, along with an underlying hypothesis that ANP32s represent an important node of physiological regulation by virtue of their diverse biochemical activities.

show abstract

Overexpression of the pp32r1 (ANP32C) oncogene or its functional mutant pp32r1Y140H confers enhanced resistance to FTY720 (Finguimod)

Cited by 11 publications

References 39 publications

The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

The emerging role of FTY720 (Fingolimod) in cancer treatment

Cracking the ANP32 whips: Important functions, unequal requirement, and hints at disease implications

Contact Info

Product

Resources

About