Anti-HLA class I antibody–mediated activation of the PI3K/Akt signaling pathway and induction of Bcl-2 and Bcl-xL expression in endothelial cells

Jin, Yiping; Fishbein, Michael C.; Said, Jonathan W.; Jindra, Peter T.; Rajalingam, Raja; Reed, Elaine F.

doi:10.1016/j.humimm.2004.01.002

Cited by 112 publications

(137 citation statements)

References 44 publications

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“…8 The role of PI3K in the control of Bcl-2 expression has been previously noted since the PI3K inhibitors LY294002 and wortmannin diminished Bcl-2 protein expression. 50,51 Studies analyzing the effect of RES on cardiovascular disease have also shown that this molecule inhibits lipid peroxidation by a pathway that involves NF-kB inactivation. 52,53 Therefore, the apoptosis induced by RES in MCF-7 cells could be mediated by Bcl-2 through a PI3K-and NF-kB-dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

205

143

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Resveratrol (RES), a chemopreventive molecule, inhibits the proliferation of tumor cells of different etiologies. We previously showed that RES alters the cell cycle and induces apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ERa)-dependent phosphoinositide 3-kinase (PI3K) pathway. Here, we analyzed signaling downstream of PI3K, to understand the mechanisms of RES-induced apoptosis. Apoptotic death by RES in MCF-7 was mediated by Bcl-2 downregulation since overexpression of this protein abolished apoptosis. Decreased Bcl-2 levels were not related to cytochrome c release, activation of caspases 3/8 or poly(ADP-ribose) polymerase proteolysis. However, RES decreased mitochondrial membrane potential and increased reactive oxygen species and nitric oxide production. NF-kB, a regulator of Bcl-2 expression, and calpain protease activity, a regulator of NF-kB, were both inhibited by RES. The patterns for NFkB and calpain activities followed that of PI3K and were inhibited by LY294002. NF-kB inhibition coincided with diminished MMP-9 activity and cell migration. These data suggest that RES-induced apoptosis in MCF-7 could involve an oxidative, caspase-independent mechanism, whereby inhibition of PI3K signaling converges to Bcl-2 through NF-kB and calpain protease activity. Therefore, Bcl-2 and NF-kB could be considered potential targets for the chemopreventive activity of RES in estrogen-responsive tumor cells. ' 2005 Wiley-Liss, Inc.Key words: resveratrol; caspase; Bcl-2; NF-kB; apoptosis Among natural compounds with beneficial effects on human health, RES (3,4 0 ,5-trihydroxystilbene) has attracted considerable interest. This molecule, present at relevant concentrations in red wine, 1 has been associated with a lower incidence of cardiovascular disease. Different studies have also suggested a beneficial effect of RES in cancer since it inhibits proliferation and promotes death in tumor cell lines of different origins, 2-4 and, in vivo, suppresses the formation of skin 5 and mammary gland 6 tumors in rodent models of carcinogenesis.We, as well as other laboratories, have found that the ability of RES to inhibit cell viability and proliferation in the human breast cancer cell lines MCF-7 and MDA-MB-231 was unrelated to ERa status. 7,8 However, apoptotic cell death was present only in ERapositive MCF-7 and involved cell-specific regulation of the G 1 /S and G 2 /M transitions of the cell cycle. 2,8 RES properties are related to ERa since this compound has estrogenic or antiestrogenic activities depending on its concentration and the phenotype of the target cell. 9,10 ERa, in addition to its nuclear role as a transcription factor, is involved in regulating the PI3K pathway, which controls cell growth, proliferation and apoptosis. [11][12][13] In MCF-7 cells, RES induced a biphasic pattern of PI3K activity that increased at low concentrations and decreased at high concentrations. Activation of downstream PI3K effectors PKB/AKT and GSK-3 closely followed the pattern of PI3K activity. 14 The ...

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Section: Discussionmentioning

confidence: 99%

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Pozo‐Guisado

Merino

Mulero‐Navarro

et al. 2005

Intl Journal of Cancer

205

143

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“…5C). Akt mediates prosurvival and anti-apoptosis by upregulating Bcl-2 (15,33). Because we observed that exposure of EC to rapamycin blocked class I-mediated phosphorylation of Akt, we reasoned that rapamycin may also block class I-induced up-regulation of the anti-apoptotic protein Bcl-2.…”

Section: Rapamycin Inhibits Class I-induced Phosphorylation Of Akt Atmentioning

confidence: 98%

“…6A Src kinases were shown to associate with FAK in response to class I ligation and promote maximal FAK activation (14). Additionally, with the recruitment of Src into a FAK-Src signaling complex, Src facilitates phosphorylation of many FAK-associated proteins, including PI3K, Akt, and paxillin (13,15). FAK plays a critical role in cell migration, cytoskeletal rearrangements, and cell survival (34 -36).…”

Section: Mtor and S6k Are Downstream Targets Of Src And Fak In The Mhmentioning

confidence: 99%

“…Engagement of class I molecules by anti-HLA Abs also stimulates phosphorylation of Src, focal adhesion kinase (FAK), and paxillin and assembly of focal adhesions and activation of the PI3K/Akt pathway (13,14). The phosphorylation of PI3K and Akt leads to up-regulation of anti-apoptotic Bcl-2 and Bcl-x L protein expression in EC (15). Ligation of MHC class I molecules phosphorylates S6 ribosomal protein (S6RP), a downstream target of mammalian target of rapamycin (mTOR) complex 1 (mTORC1), suggesting a role for this pathway in cell proliferation and protein synthesis.…”

mentioning

confidence: 99%

“…In vivo evidence that anti-class I Abs initiate a cell proliferation signaling cascade was provided by immunostaining of cardiac transplant biopsies with evidence of AMR. Biopsies from heart allografts diagnosed with AMR showed increased expression of phosphorylated S6RP suggesting that class I signaling may elicit cell proliferation via the mTOR/S6RP pathway (15,16).…”

mentioning

confidence: 99%

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HLA Class I Antibody-Mediated Endothelial Cell Proliferation via the mTOR Pathway

Jindra¹,

Jin²,

Rozengurt

et al. 2008

The Journal of Immunology

Self Cite

145

144

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Anti-HLA Abs have been shown to contribute to the process of transplant vasculopathy by binding to HLA class I molecules expressed by the endothelial and smooth muscle cells of the graft and transducing intracellular signals that elicit cell proliferation. The aim of this study was to determine the role of mammalian target of rapamycin (mTOR) in HLA class I-induced endothelial cell proliferation and to explore in depth the relationship between mTOR complexes and their downstream targets following ligation of HLA class I molecules by anti-HLA Abs. We used small interfering RNA technology to abrogate mTOR, rapamycin-insensitive companion of mTOR (rictor), or regulatory associated protein of mTOR (raptor) to study the function of these gene products to activate proteins involved in MHC class I-induced cell proliferation and survival. Knockdown of mTOR inhibited class I-mediated phosphorylation of proteins downstream of mTOR complex 1 and mTOR complex 2. Furthermore, knockdown of mTOR, rictor, or raptor blocked HLA class I-induced endothelial cell proliferation. Long-term pretreatment with the mTOR inhibitor rapamycin significantly blocked both mTOR-raptor and mTOR-rictor complex formation. Interestingly, rapamycin also blocked class I-induced Akt phosphorylation at Ser473 and Bcl-2 expression. These results support the role of anti-HLA Abs in the process of transplant vasculopathy and suggest that exposure of the graft endothelium to anti-HLA Abs may promote proliferation through the mTOR pathway.

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Transplant Antigen Biology

Rajalingam

Zhang

Cecka

et al. 2014

Textbook of Organ Transplantation

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Anti-HLA class I antibody–mediated activation of the PI3K/Akt signaling pathway and induction of Bcl-2 and Bcl-xL expression in endothelial cells

Cited by 112 publications

References 44 publications

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

HLA Class I Antibody-Mediated Endothelial Cell Proliferation via the mTOR Pathway

Transplant Antigen Biology

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