Expression of MAGE and GAGE genes in medulloblastoma and modulation of resistance to chemotherapy

Abstract

<jats:sec> <jats:title>Object</jats:title> <jats:p>Cancer testis antigens (CTAs) were initially identified by their ability to elicit autologous T-cell–mediated immune responses in patients with melanoma. The <jats:italic>CTA</jats:italic> genes are widely expressed in a variety of human cancers, such as melanoma, breast cancer, lung cancer, esophageal cancer, and hepatocellular carcinoma; however, their expression in pediatric brain tumors, such as medulloblastoma (MB), has not been the subject of in-depth analysis. The MAGE proteins are members of the CTA family and have been shown to correlate with tumor development, aggressive clinical course, or resistance to chemotherapeutic agents. The authors undertook this study to examine the expression and role of MAGE proteins in human MB cell lines and specimens.</jats:p></jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>From a transcriptional profiling study in which 47,000 genes in MB cell lines were examined, the authors identified members of the <jats:italic>MAGE</jats:italic> and <jats:italic>GAGE</jats:italic> families as being highly expressed. A series of MB tumors was examined using both immunohistochemistry and Western blot analysis with antibodies to the MAGE-A family, MAGE-A1, and GAGE proteins.</jats:p></jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Western blot analysis showed expression of these 3 proteins (MAGE-A family, MAGE-A1, and GAGE) in 62, 46, and 84%, respectively, of MB specimens examined. In addition, a correlation was observed between the expression of <jats:italic>MAGE</jats:italic> and <jats:italic>GAGE</jats:italic> genes and resistance of MB cells to chemotherapeutic agents. The functional significance of this correlation was examined in MAGE knockdown studies, and increased drug-induced cytotoxicity was observed in UW426 MB cells following treatment with chemotherapeutic drugs. Cleaved caspase-3 was found in UW426/MAGE small interfering (si)RNA–inhibited cells treated with cisplatin, but not in UW426 cells treated with cisplatin alone at the same concentration.</jats:p></jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>These data show that MAGE and GAGE family members are expressed in MB cell lines and specimens, and that inhibition of <jats:italic>MAGE</jats:italic> and <jats:italic>GAGE</jats:italic> genes by siRNA increases apoptosis of MB cells and sensitizes them to certain chemotherapeutic agents such as cisplatin and etoposide.</jats:p></jats:sec>

Impact of MAGE-A antigens on taxane response in oral squamous cell carcinoma

“…A recent study investigating the influence of cancer/testis antigens on t-cell-mediated immune response in patients suffering from medulloblastoma also found an impact of MAge-A expression level on the response to chemotherapeutic drugs cisplatin and etoposide (16). these findings are relevant to oral squamous cell carcinoma, since cisplatin is one of the pillars of anti-neoplastic treatment of this tumour.…”

Knockdown of CABYR-a/b Increases Chemosensitivity of Human Non–Small Cell Lung Cancer Cells through Inactivation of Akt

“…It has been reported that the paclitaxel-sensitive human ovarian cancer cell line OVCAR8 overexpresses MAGE2 and MAGE6, which leads to enhanced resistance of these cells to paclitaxel and doxorubicin but not other drugs, such as topotecan and cisplatin (5). Furthermore, the inhibition of MAGE-A and GAGE expression was shown to increase apoptosis in medulloblastoma cells and to sensitize these cells to cisplatin and etoposide (6). Similarly, the downregulation of CAGE in the drugresistant human melanoma cell line Malme3M and the human hepatic cancer cell line SWU387 was found to increase drug sensitivity resulting from apoptosis induction (7).…”

The Cancer/Testis Antigen Prostate-associated Gene 4 (PAGE4) Is a Highly Intrinsically Disordered Protein

“…Decreasing PAGE4 Attenuates Cell Survival-Up-regulation of several CTAs including PAGE4 is associated with drug resistance in cancer cells (41)(42)(43)(44). Given the intrinsic nature of IDPs to engage in promiscuous interactions and the presence of a putative DNA-binding region in PAGE4, we hypothesized that PAGE4 may play a critical role in cancer cells by mitigating the genotoxic stress caused by cytotoxic drugs either by interacting with key proteins or by directly binding DNA (or both).…”