Molecular Characterization of Zoledronic acid Induced Growth Inhibition in Cancer
Zoledronic acid is a nitrogen-containing bisphosphonate widely used in the treatment of bone metastasis secondary to breast cancer. In addition, current clinical trials suggest direct antitumor effects, which may reduce the risk of overall disease progression in breast cancer patients. Consisten...
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| Format: | Doctoral Thesis |
| Language: | English |
| Published: |
Philipps-Universität Marburg
2010
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| Online Access: | PDF Full Text |
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| Summary: | Zoledronic acid is a nitrogen-containing bisphosphonate widely used in the
treatment of bone metastasis secondary to breast cancer. In addition,
current clinical trials suggest direct antitumor effects, which may reduce
the risk of overall disease progression in breast cancer patients.
Consistently, recent experimental approaches have demonstrated strong
antiproliferative and apoptotic effects in various human cancer cells,
although the molecular mechanisms remained elusive.
This study was conducted to identify key mechanisms underlying the
growth suppressor activity of zoledronic acid in epithelial cancer. For this
purpose, we employed an extensive series of cellular, molecular as well as
biochemical studies and uncovered the existence of a nuclear GSK3β-
NFATc2 stabilization pathway that is target for inactivation by zoledronic
acid during growth suppression. GSK3β labels nuclear NFAT through
phosphorylation of three phosphoserines (Ser 215, Ser 219 and Ser 223)
residues located within the N-terminal SP2 motif of the factor, and this
post-translational modification protects the factor from ubiquitination and
degradation. The phosphoserine sequences are highly conserved among
species and are identical to the previously reported “phospho-degron”
elements through which GSK3β labels other key cell cycle regulators for
subsequent ubiquitination and proteasomal degradation.
Here, we show that GSK3β can make use of the “phospho-degron”
elements to stabilize rather than proteolyse mitogenic transcription
factors, and thus GSK3β exerts pro-proliferative functions through
stabilization of NFATc2 levels in cancer. Treatment with zoledronic acid,
however, inhibits GSK3β kinase activity, thus disrupts NFATc2
phosphorylation and stabilization in the nucleus, and finally allows the 26S proteasomal machinery to target NFATc2 for degradation. Mechanistically,
HDM2, the human homologue of the E3-ligase MDM2, accumulates in the
nucleus upon treatment binds to NFATc2 and transfers ubiquitin to lysines
K-684 and K-897. Ubiquitination of K-684 and K-897 requires an
unphosphorylated status of NFATc2 in the nucleus and is key for the
subsequent recognition and degradation by the 26S proteasome. The net
cellular outcome of GSK3β -NFATc2 pathway disruption and degradation of
the transcription factor is a progredient halt of cancer cells at the G1 cell
cycle phase. Together, this study uncovers a key pathway in cancer growth
control that is aimed for inactivation by zoledronic acid. From the medical
point of view, we believe that these findings significantly contribute to a
better understanding of the biochemical basis underlying one of the most
promising and exciting new treatment for malignant disease. |
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| DOI: | 10.17192/z2010.0675 |