Novel role for the N-terminus domain of the a2 isoform of vacuolar ATPase in interleukin-1β production

Ntrivalas, Evangelos; Derks, Richard; Gilman‐Sachs, Alice; Kwak‐Kim, Joanne; Levine, Rita; Beaman, Kenneth D.

doi:10.1016/j.humimm.2007.02.010

Cited by 17 publications

(21 citation statements)

References 29 publications

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“…Earlier studies associated a number of immunological effects with a2V expression (20,21) as well as with the recombinantly expressed peptide (10). In similar experiments, MDA cocultured with PBMCs induced the most IL-1b compared with the other cell lines; this correlated with the relatively high a2V expression in MDA cells (Fig.…”

Section: A2v-atpase Utilizes Microvesicles In Il-1b Inductionmentioning

confidence: 69%

“…The resulting peptide (a2NTD) had inflammatory properties. Further experiments showed that monocytes responded to a2NTD stimulation (10).…”

mentioning

confidence: 98%

“…Previous experiments that investigated whether V-ATPase played a role in CRI produced promising results (9,10). The hypothesis generated from those experiments was that the Nterminal domain of the a2 isoform vacuolar ATPase (a2V) was cleaved from the a2 subunit.…”

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confidence: 99%

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Tumor-Associated a2 Vacuolar ATPase Acts As a Key Mediator of Cancer-Related Inflammation by Inducing Pro-Tumorigenic Properties in Monocytes

Kwong

Gilman‐Sachs

Beaman

2011

The Journal of Immunology

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Cancer-related inflammation profoundly affects tumor progression. Tumor-associated macrophages (TAMs) are known regulators of that inflammation, but the factors that initiate cancer-related inflammation are poorly understood. Tumor invasiveness and poor clinical outcome are linked to increased expression of cell surface-associated vacuolar adenosine triphosphatases. The a2 isoform vacuolar adenosine triphosphatase is found on the surface on many solid tumors, and we have identified a peptide cleaved from a2 isoform vacuolar adenosine triphosphatase called a2NTD. a2NTD has properties necessary to induce monocytes into a pro-oncogenic TAM phenotype. The peptide upregulated both pro- and anti-inflammatory mediators. These included IL-1β and IL-10, which are important in promoting inflammation and immune escape by tumor cells. The secretion of inflammatory cytokine IL-1β was dependent on ATP, K+ efflux, and reactive oxygen species, all mediators that activate the inflammasome. These findings describe a mechanism by which tumor cells affect the maturation of TAMs via a nontraditional cytokine-like signal, the a2NTD peptide.

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Section: A2v-atpase Utilizes Microvesicles In Il-1b Inductionmentioning

confidence: 69%

“…The resulting peptide (a2NTD) had inflammatory properties. Further experiments showed that monocytes responded to a2NTD stimulation (10).…”

mentioning

confidence: 98%

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Tumor-Associated a2 Vacuolar ATPase Acts As a Key Mediator of Cancer-Related Inflammation by Inducing Pro-Tumorigenic Properties in Monocytes

Kwong

Gilman‐Sachs

Beaman

2011

The Journal of Immunology

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“…V‐ATPase ‘V0a’ subunit is the major pH sensing unit and additionally plays a crucial role in subcellular localization of this proton pump and exists in four different isoforms (a1/a2/a3/a4) (Forgac M, 2007). Our previous studies have highlighted the profound role of ‘V0a2’ isoform in tumor progression, metastasis and immuno‐modulation (Kwong et al., 2011; Katara et al., 2014; Ntrivalas et al., 2007a,b; Katara et al., 2015; Kulshrestha et al., 2015). In context of ovarian cancer, our recent study demonstrated a distinct surface expression of V0a2, the inhibition of which reduced tumor cell migration (Kulshrestha et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of tumor cell associated Vacuolar‐ATPase ‘a2’ isoform overcomes cisplatin resistance in ovarian cancer cells

et al. 2016

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Development of resistance to platinum compounds significantly hinders successful ovarian cancer (OVCA) treatment. In tumor cells, dysregulated pH gradient across cell membranes is a key physiological mechanism of metastasis/chemo-resistance. These pH alterations are mediated by aberrant activation of key multi-subunit proton pumps, Vacuolar-ATPases (V-ATPases). In tumor cells, its 'a2' isoform (V-ATPase-V0a2) is a component of functional plasma-membrane complex and promotes tumor invasion through tumor-acidification and immuno-modulation. Its involvement in chemo-resistance has not been studied. Here, we show that V-ATPase-V0a2 is over-expressed in acquired-cisplatin resistant OVCA cells (cis-A2780/cis-TOV112D). Of all the 'a' subunit isoforms, V-ATPase-V0a2 exhibited an elevated expression on plasma membrane of cisplatin-resistant cells compared to sensitive counterparts. Immuno-histochemistry revealed V-ATPase-V0a2 expression in both low grade (highly drug-resistant) and high grade (highly recurrent) human OVCA tissues indicating its role in a centralized mechanism of tumor resistance. In cisplatin resistant cells, shRNA mediated inhibition of V-ATPase-V0a2 enhanced sensitivity towards both cisplatin and carboplatin. This improved cytotoxicity was mediated by enhanced cisplatin-DNA-adduct formation and suppressed DNA-repair pathway, leading to enhanced apoptosis. Suppression of V0a2 activity strongly reduced cytosolic pH in resistant tumor cells, which is known to enhance platinum-associated DNA-damage. As an indicator of reduced metastasis and chemo-resistance, in contrast to plasma membrane localization, a diffused cytoplasmic localization of acidic vacuoles was observed in V0a2-knockdown resistant cells. Interestingly, pre-treatment with monoclonal V0a2-inhibitory antibody enhanced cisplatin cytotoxicity in resistant cells. Taken together, our findings suggest that the isoform specific inhibition of V-ATPase-V0a2 could serve as a therapeutic strategy for chemo-resistant ovarian carcinoma and improve efficacy of platinum drugs.

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“…The second is the cleavage and release of a2NTD (N-terminal portion of a2V) from the a2V polypeptide. This peptide is responsible for the selective increase in transcription and secretion of several different cytokines such as IL1B, IL1A, LIF, IL10, and chemokine (MCP1/CCL2), which are important in maintaining the immune response in pregnancy [6,15,16].…”

Section: Introductionmentioning

confidence: 99%

Placental ATPase Expression Is a Link Between Multiple Causes of Spontaneous Abortion in Mice

Jaiswal¹,

Gilman‐Sachs²,

Chaouat³

et al. 2011

Biology of Reproduction

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The a2 isoform of vacuolar ATPase (ATP6V0A2 referred to as a2V) plays a pivotal role in successful pregnancy and provides a microenvironment to maintain the delicate immunological balance at the feto-maternal interaction. We studied the expression of a2V mRNA in embryos and placenta of abortion-prone (female CBA × male DBA) murine matings or LPS (lipopolysaccharide)-treated mice. The expression of a2V was significantly higher in the placentas of nonabortion-prone (female BALB/c × male BALB/c and female CBA × male BALB/c) matings compared with the abortion-prone (female CBA × male DBA) mating. The expression of a2V was significantly decreased in the placentas treated with LPS in both female CBA × male DBA and female BALB/c × male BALB/c mating combinations with increased Lif, Il1b, and Tnf expression in the placenta. Decreased expression of a2V in the placenta is directly correlated with high percentages of pregnancy loss in abortion-prone mating (female CBA × male DBA) as well as in LPS-treated animals. The normal expression of placental a2V on Day 16 in the nonabortion-prone matings correlated with higher Mcp1 (monocyte chemotactic protein 1) gene expression, markedly higher infiltration of M1 and M2 macrophages, and no significant polarization patterns (M1/M2 = 1.2-1.6). However, in the abortion-prone mating, decreased placental a2V expression correlated with significantly lower Mcp1 gene expression with less infiltration of M1 and M2 macrophages and with polarization patterns skewed to M1 phenotypes (M1/M2 = 3.9-4.2). These data indicate that the higher expression of placental a2V is associated with dynamic infiltration of M1 and M2 macrophages through the induction of Mcp1 expression. This strengthens our hypothesis that a2V regulates the delicate cytokine and chemokine networks that coordinate the recruitment of macrophages for successful placental development and growth at the feto-maternal interface.

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Novel role for the N-terminus domain of the a2 isoform of vacuolar ATPase in interleukin-1β production

Cited by 17 publications

References 29 publications

Tumor-Associated a2 Vacuolar ATPase Acts As a Key Mediator of Cancer-Related Inflammation by Inducing Pro-Tumorigenic Properties in Monocytes

Tumor-Associated a2 Vacuolar ATPase Acts As a Key Mediator of Cancer-Related Inflammation by Inducing Pro-Tumorigenic Properties in Monocytes

Selective inhibition of tumor cell associated Vacuolar‐ATPase ‘a2’ isoform overcomes cisplatin resistance in ovarian cancer cells

Placental ATPase Expression Is a Link Between Multiple Causes of Spontaneous Abortion in Mice

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