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The biological function of Cancer-testis antigen MAGE-C2/CT10 in Multiple Myeloma
Charakterisierung der Rolle des Cancer-Testis-Antigens MAGE-C2/CT10 im Multiplen Myelom
Dokument 1.pdf (19.756 KB)
Freie Schlagwörter (Englisch):
Multiple Myeloma , Cancer-testis antigens
Fiedler, Walter (Prof. Dr.)
Tag der mündlichen Prüfung:
Kurzfassung auf Englisch:
Cancer-testis antigens belonging to the MAGE class I family of genes, such as MAGE-C2/CT10, are commonly expressed in Multiple Myeloma (MM). Expression of MAGE class I genes in MM is associated with aggressive disease, resistance to chemotherapy and a poor clinical outcome, suggesting that MAGE genes may confer a survival advantage on myeloma cells. MAGE-C2/CT10 is thought to be an excellent candidate for cancer immunotherapy based on its myeloma-specific expression. It was shown that MAGE-C2/CT10 enhances p53 polyubiquitination and proteasome-dependent degradation which may impair p53-dependent apoptosis. However, in spite of its frequent expression, the biological function of MAGE-C2/CT10 in malignant plasma cells has never been elucidated.
Therefore, by using the RNA interference approach, we aimed to investigate, in vitro, the impacts of MAGE-C2/CT10 silencing on the survival of tumor cells derived from MM patients.
We found that MAGE-C2/CT10 silencing inhibited the proliferation and anchorage-independent growth of myeloma cell lines, irrespective of the functional status of p53. The anti-proliferative effect of MAGE-C2/CT10 silencing was due to a decrease of cells in the S phase, a cell cycle arrest at both G0/G1 and G2/M transitions, and an increase in the subG0/G1 diploid population based on an initiation of apoptotic cell death. Importantly, MAGE-C2/C10 overexpression was able to rescue the anti-proliferative effect of MAGE-C2/CT10 depletion and protected cells from apoptotic cell death. At the molecular level, the loss of MAGE-C2/CT10 expression increased the phosphorylation of the histone variant H2A.X at Ser139, which is a sensitive indicator of DNA damage, enhanced the constitutive activation of the ATM/ATR-CHK1/CHK2 DNA damage response and led to an accumulation of the endogenous level of p53 protein. The stabilization and activation of p53, through phosphorylation at Ser20 correlated with an up-regulation of p21 (WAF1/CIP1) and GADD45Aα, which are the main mediators of p53-dependent and independent G1/S and G2/M cycle arrest, respectively, and a two-fold increase in the expression of the pro-apoptotic Bcl-2 genes BAX and BAK, being the effectors of p53-dependent and independent intrinsic apoptotic pathway in response to DNA damage.
Collectively, our findings, strongly, support an anti-apoptotic function of MAGE-C2/CT10 in MM through the regulation of key molecules involved in the regulation of DNA damage repair and p53-dependent and/or independent apoptotic pathways. The central role of MAGE-C2/CT10 in the biology of myeloma suggests that this CTA represents a promising target for myeloma-specific immunotherapies or other targeted modes of therapy for MM.