Melphalan and Other Anticancer Modalities Up-Regulate B7-1 Gene Expression in Tumor Cells

Sojka, Dorothy K.; Donepudi, Manjula; Bluestone, Jeffrey A.; Mokyr, Margalit B.

doi:10.4049/jimmunol.164.12.6230

Cited by 54 publications

(61 citation statements)

References 43 publications

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Section: Mechanism Of Melphalansupporting

confidence: 58%

“…Our studies revealed that within 24 h after in vitro exposure of MOPC-315 tumor cells to L-PAM, the tumor cells exhibited up-regulated B7-1 surface expression and unaltered B7-2 surface expression, which was high to start with (15). This effect of L-PAM was not restricted to MOPC-315 tumor cells, as preferential up-regulation of B7-1 surface expression was also observed within 24 h after in vitro exposure of P815 tumor cells to L-PAM (15). Subsequent studies into the mechanism through which L-PAM leads to up-regulation of B7-1 surface expression used P815 tumor cells because, unlike MOPC-315 tumor cells, P815 tumor cells do not constitutively express either the B7-1 or the B7-2 molecule on their surface (15).…”

Section: Mechanism Of Melphalanmentioning

confidence: 77%

“…To test this hypothesis, we determined initially whether in vitro exposure of MOPC-315 tumor cells from untreated mice to L-PAM results in rapid up-regulation of B7-1, but not B7-2, surface expression. Our studies revealed that within 24 h after in vitro exposure of MOPC-315 tumor cells to L-PAM, the tumor cells exhibited up-regulated B7-1 surface expression and unaltered B7-2 surface expression, which was high to start with (15). This effect of L-PAM was not restricted to MOPC-315 tumor cells, as preferential up-regulation of B7-1 surface expression was also observed within 24 h after in vitro exposure of P815 tumor cells to L-PAM (15).…”

Section: Mechanism Of Melphalanmentioning

confidence: 95%

“…Opposite expression patterns of these costimulatory molecules were observed following L-PAM therapy of MOPC-315 tumor bearers (15). Specifically, B7-1 was up-regulated at the tumor site within 24 h after L-PAM treatment (15), whereas B7-2 was up-regulated after 48 h (11), which is similar to the time of up-regulation of B7-2 expression on APC exposed to the other stimuli (12)(13)(14). In light of these observations, we considered the possibility that in contrast to B7-2, which is up-regulated indirectly by L-PAM (i.e., L-PAM induces TNF-␣ production (16) that in turn leads to up-regulation of B7-2 surface expression; Ref.…”

Section: Mechanism Of Melphalanmentioning

confidence: 99%

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Mechanism of Melphalan-Induced B7-1 Gene Expression in P815 Tumor Cells

Donepudi

Raychaudhuri

Bluestone

et al. 2001

The Journal of Immunology

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We have previously shown that exposure of P815 tumor cells to melphalan (l-phenylalanine mustard; l-PAM) leads to up-regulation of B7-1 surface expression, and this l-PAM-induced up-regulation requires de novo RNA synthesis and is associated with accumulation of B7-1 mRNA. Here we show that the effect of l-PAM on B7-1 surface expression can be mimicked by exposing P815 tumor cells to oxidative stress but not to heat shock. Moreover, the antioxidant N-acetyl-l-cysteine prevented the l-PAM-induced accumulation of B7-1 mRNA in P815 tumor cells, suggesting that reactive oxygen species are involved in the transcriptional regulation of l-PAM-induced B7-1 gene expression. Although AP-1 and NF-κB are regarded as redox-sensitive transcription factors and the promoter/enhancer region of the B7-1 gene contains an AP-1 and an NF-κB binding site, exposure of P815 tumor cells to l-PAM led to rapid and transient activation only of NF-κB, but not AP-1, that bound specifically to a probe containing the respective binding site in the murine or human B7-1 gene. Moreover, exposure of P815 tumor cells to a cell-permeable peptide that selectively inhibits NF-κB activation by blocking the activation of the IκB-kinase complex was found to inhibit the l-PAM-induced B7-1 mRNA accumulation, indicating that NF-κB activation is essential for the l-PAM-induced B7-1 gene expression. Taken together, these results indicate that l-PAM leads to activation of B7-1 gene expression by activating NF-κB via a pathway that involves reactive oxygen species.

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Section: Mechanism Of Melphalansupporting

confidence: 58%

Section: Mechanism Of Melphalanmentioning

confidence: 77%

Section: Mechanism Of Melphalanmentioning

confidence: 95%

Section: Mechanism Of Melphalanmentioning

confidence: 99%

See 2 more Smart Citations

Mechanism of Melphalan-Induced B7-1 Gene Expression in P815 Tumor Cells

Donepudi

Raychaudhuri

Bluestone

et al. 2001

The Journal of Immunology

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“…B7-1 (CD80) is expressed in MOPC315 and P815 cells exposed to lowdose melphalan, as well as in splenic lymphocytes, and expression of these costimulatory molecules plays a crucial role in enhancing tumor immunity in these systems (63)(64)(65). Similarly, DAAs may confer upon L1210 lymphoma the ability to act as APCs for their own tumor-associated Ags via up-regulation of MHC class II and costimulatory molecules.…”

Section: Role Of Ciita In Daa-induced Increases In Immunogenicity Of mentioning

confidence: 99%

DNA Alkylating Agents Alleviate Silencing of Class II Transactivator Gene Expression in L1210 Lymphoma Cells

Murphy

Holtz

Lewandowski

et al. 2002

The Journal of Immunology

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MHC class II (Ia) Ag expression is inversely correlated with tumorigenicity and directly correlated with immunogenicity in clones of the mouse L1210 lymphoma (1 ). Understanding the mechanisms by which class II Ag expression is regulated in L1210 lymphoma may facilitate the development of immunotherapeutic approaches for the treatment of some types of lymphoma and leukemia. This study demonstrates that the variation in MHC class II Ag expression among clones of L1210 lymphoma is due to differences in the expression of the class II transactivator (CIITA). Analysis of stable hybrids suggests that CIITA expression is repressed by a dominant mechanism in class II-negative L1210 clones. DNA-alkylating agents such as ethyl methanesulfonate and the chemotherapeutic drug melphalan activate CIITA and class II expression in class II negative L1210 cells, and this effect appears to be restricted to transformed cell lines derived from the early stages of B cell ontogeny. Transient transfection assays demonstrated that the CIITA type III promoter is active in class II− L1210 cells, despite the fact that the endogenous gene is not expressed, which suggests that these cells have all of the transacting factors necessary for CIITA transcription. An inverse correlation between methylation of the CIITA transcriptional regulatory region and CIITA expression was observed among L1210 clones. Furthermore, 5-azacytidine treatment activated CIITA expression in class II-negative L1210 cells. Collectively, our results suggest that 1) CIITA gene expression is repressed in class II− L1210 cells by methylation of the CIITA upstream regulatory region, and 2) treatment with DNA-alkylating agents overcomes methylation-based silencing of the CIITA gene in L1210 cells.

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