A AN NN NA AL LS S RES ARTICLE a key role in tumor progression [13]. Over the years, several studies have aimed at understanding the mechanisms governing the aggressive behavior of GBM, but it still remains elusive [14-17]. One of the most common signaling cascades dysregulated in cancer is MEK-ERK pathway, which is involved in cancer cell survival [18]. Similarly, in malignant gliomas the RAS/ RAF/MEK/ERK pathway is aberrantly activated [19]. An earlier study has shown that the ablation of the MEK1/2 kinases and/or ERK1/2 kinases in mice model of non-small cell carcinoma effectively prevented K-RAS-driven tumor development [20]. There are conflicting reports on the role of ERK1/2 pathway on glioma cells. One study demonstrated that transient activation of ERK1/2 by human chorionic gonadotropin β resulted in migration and invasion [21], while the other study reported that sustained activation of ERK1/2 by Sulforaphane inhibits migration and invasion of glioma cells [17]. Nonetheless, these findings suggest the importance of ERK signaling in growth of glioma necessitating the need for further studies to decipher ERK pathway in glioma biology. With this viewpoint the current study was designed to investigate the effect of inhibition of MEK-ERK1/2 signaling by PD98059 and U0126 on the growth and migration of glioma cells as well as their adhesion to ECM.

Cancer cells are highly metabolically active and produce high levels of reactive oxygen species (ROS). Drug resistance in cancer cells is closely related to their redox status. The role of ROS and its impact on cancer cell survival seems far from elucidation. The mechanisms through which glioblastoma cells overcome aberrant ROS and oxidative stress in a milieu of hypermetabolic state is still elusive. We hypothesize that the formidable growth potential of glioma cells is through manipulation of tumor microenvironment for its survival and growth, which can be attributed to an astute redox regulation through a nexus between activation of N-methyl-D-aspartate receptor (NMDAR) and glutathione (GSH)-based antioxidant prowess. Hence, we examined the NMDAR activation on intracellular ROS level, and cell viability on exposure to hydrogen peroxide (H 2 O 2 ), and antioxidants in glutamate-rich microenvironment of glioblastoma. The activation of NMDAR attenuated the intracellular ROS production in LN18 and U251MG glioma cells. MK-801 significantly reversed this effect. On evaluation of GSH redox cycle in these cells, the level of reduced GSH and glutathione reductase (GR) activity were significantly increased. NMDAR significantly enhanced the cell viability in LN18 and U251MG glioblastoma cells, by attenuating exogenous H 2 O 2 -induced oxidative stress, and significantly increased catalase activity, the key antioxidant that detoxifies H 2 O 2 . We hereby report an unexplored role of NMDAR activation induced protection of the rapidly multiplying glioblastoma cells against both endogenous ROS as well as exogenous oxidative challenges. We propose potentiation of reduced GSH, GR, and catalase in glioblastoma cells through NMDAR as a novel rationale of chemoresistance in glioblastoma.