Role of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cells

Abstract

Testicular germ cell tumour (TGCT) is the most common malignancy in young males. Although most TGCTs are sensitive to cisplatin-based chemotherapy, significant numbers of TGCT patients still relapse and die each year because of the development of resistance to cisplatin. Previously, we first reported that a key regulator of the mitotic checkpoint, mitotic arrest deficient-2 (MAD2), was a mediator of cisplatin sensitivity in human cancer cells. In this study, we investigated whether MAD2 played a role in cellular sensitivity to cisplatin in TGCT cells and the underlying molecular mechanisms responsible. Using 10 TGCT cell lines, we found that increased MAD2 expression was correlated with cellular sensitivity to cisplatin, which was associated with activation of the MEK pathway. Treatment of cells expressing high levels of MAD2 with an MEK inhibitor, U0126, led to cellular protection against cisplatininduced apoptosis. Inactivation of MAD2 by transfecting a dominant-negative construct in TGCT cells with high levels of MAD2 resulted in the suppression of MEK pathway and resistance to cisplatin-induced cell death. These results support previous suggestion on the involvement of mitotic checkpoint in DNA damage response in human cancer cells and demonstrate a possible molecular mechanism responsible for the MAD2-mediated sensitivity to cisplatin in TGCT cells. Our results also suggest that downregulation of MAD2 may be an indicator for identification of TGCT cancer cells that are potentially resistant to cisplatin-based therapy.

Expression of mitotic-arrest deficiency 2 predicts the efficacy of neoadjuvant chemotherapy for locally advanced uterine cervical cancer

“…The overexpression of MAD2 has also been observed in a number of types of human cancer (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and appears to correlate with a variety of clinicopathological characteristics, such as metastasis and prognosis (13)(14)(15)(16)(17)(18)(19). Reduced expression of MAD2 has also been reported in certain human cancers (4,21) and is associated with resistance to chemotherapy using microtubuletargeting agents or DNA-damaging agents (22,23).…”

“…Certain studies have suggested a correlation between the overexpression of MAD2 and a variety of clinicopathological characteristics, such as histological grade (differentiation), metastasis and prognosis (13)(14)(15)(16)(17)(18)(19). However, reduced expression of MAD2 occurs in certain types of human cancer (4,21) and is associated with in vitro resistance to chemotherapy using microtubule-targeting agents or DNA-damaging agents (22,23).…”

Increased ERK activation and cellular drug accumulation in the enhanced cytotoxicity of folate receptor-targeted liposomal carboplatin

“…Several research groups have reported the active role of ERK in mediating the cytotoxicity of cisplatin and carboplatin (29)(30)(31)(32)(33)(34), and these studies have provided the basis to probe ERK activation as a molecular event in mediating the cytotoxic effect of carboplatin delivered via FRT liposomes. Our results demonstrated significantly higher ERK activation by FRT carboplatin liposomes as compared to free form and NT liposomes.…”

“…Several studies have reported the role of ERK activation in cisplatin-and carboplatin-induced apoptosis (29)(30)(31)(32)(33)(34). It is thus interesting to probe if ERK activation would be observed in KB cells upon exposure to FRT carboplatin liposomes, which in turn, mediated the cytotoxic effect of these liposomes.…”

Targeting anthracyclines in early breast cancer: new candidate predictive biomarkers emerge

“…This subsequently leads to an accumulation of securin (PTTG1) and cyclin B, thereby prolonging progression of mitosis to anaphase. Recent research has shown expression of MAD2, a direct target of the E2F family, to be associated with increased sensitivity to DNA-damaging agents (Cheung et al, 2005;Du et al, 2006;Fung et al, 2006).…”