Molecular mechanisms of the antiangiogenic and antitumor effects of mycophenolic acid.
The relative risk for the development of malignancies following solid organ transplantation seems to be decreased in patients treated with the immunosuppressive agent mycophenolic acid (MPA). However, the molecular mechanisms of the antineoplastic effects of MPA are not completely understood. Here, we report that human endothelial cells and fibroblasts are highly sensitive to MPA treatment. We found that U87 glioblastoma cells were resistant to MPA treatment in vitro. However, U87 tumor growth was markedly inhibited in vivo in BALB/c nude mice, suggesting that MPA exerted its antitumor effects via modulation of the tumor microenvironment. Accordingly, microvascular density and pericyte coverage were markedly reduced in MPA-treated tumors in vivo. Using functional in vitro assays, we showed that MPA potently inhibited endothelial cell and fibroblast proliferation, invasion/migration, and endothelial cell tube formation. To identify the genetic participants governing the antiangiogenic and antifibrotic effects of MPA, we performed genome-wide transcriptional analysis in U87, endothelial and fibroblast cells at 6 and 12 h after MPA treatment. Network analysis revealed a critical role for MYC signaling in endothelial cells treated with MPA. Moreover, we found that the antiangiogenic effects of MPA were organized by coordinated communications between MYC and NDRG1, YYI, HIF1A, HDAC2, CDC2, GSK3B, and PRKACB signaling. The regulation of these "hub nodes" was confirmed by real-time quantitative reverse transcription-PCR and protein analysis. The critical involvement of MYC in the antiangiogenic signaling of MPA was further shown by gene knockdown experiments. Together, these data provide a molecular basis for the antiangiogenic and antifibrotic effects of MPA, which warrants further clinical investigations.
Department of Radiation Oncology, German Cancer Research Center, Heidelberg, Germany. Sophie.Domhan@med.uni-heidelberg.de
Sophie
S
Domhan
Stefan
S
Muschal
Christian
C
Schwager
Christian
C
Morath
Ute
U
Wirkner
Wilhelm
W
Ansorge
Christian
C
Maercker
Martin
M
Zeier
Peter E
PE
Huber
Amir
A
Abdollahi
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009173:Mycophenolic Acid / Q000494:pharmacology*; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D016271:Proto-Oncogene Proteins c-myc; D009173:Mycophenolic Acid