Inhibition of the met receptor tyrosine kinase signaling enhances the chemosensitivity of glioma cell lines to CDDP through activation of p38 MAPK pathway

Abstract

The Met receptor tyrosine kinase is known to be overexpressed in many solid tumors and plays a crucial role in tumor invasive growth and metastasis. In this study, we showed that hepatocyte growth factor-induced Met activation as well as Met-dependent downstream signaling of AKT and p44/42 mitogen-activated protein kinase (MAPK) could be efficiently blocked by TAT-coupled carboxyl-terminal tail peptide of Met receptor (TCTP), and inactivation of Met signaling significantly enhanced the sensitivity of T98G and U251 glioma cells to cisdiaminedichloroplatinum (CDDP, cisplatin). However, neither phosphoinositide 3-kinase/AKT inhibitor LY294002 nor p44/42 MAPK inhibitor PD98059 alone or combined could imitate the effect of TCTP on chemosensitivity enhancement of T98G cells to CDDP, indicating that Met-dependent inactivation of AKT and p44/42 MAPK signaling was not the main cause for the increased chemosensitivity to CDDP. Further studies revealed that TCTP significantly activated p38 MAPK in T98G and U251 cell lines. Activation of p38 MAPK by sorbitol pretreatment resembled the sensitization effects, whereas inhibition of p38 MAPK activation by its inhibitor SB202190 counteracted the sensitization effects induced by TCTP. Therefore, p38 MAPK activation was one of the major causes for the increased chemosensitivity to CDDP induced by Met inactivation. Taken together, the study indicated that Met receptor played an important role in regulating cell response to chemotherapy and suggested that inhibition of Met signaling could be used in combination with other chemotherapeutic regimens in treatment of tumor patients.

p38γ overexpression in gliomas and its role in proliferation and apoptosis

“…As to human gliomas, researches indicated that the tumor occurrence was closely related to the MKK3/p38 pathway activation, and inhibition of p38 by LY479754 greatly sensitized arrested glioma cells to cytotoxic therapies15. Studies also detectd that p38 activation was one of the major causes for the increased chemosensitivity to CDDP on glioma cells23 Moreover, p38 inhibition was found to strongly reduce invasion of U251 glioblastoma cells in an inflammatory microenvironment24.…”

Heat stress: A risk factor for skin carcinogenesis

“…SIRT1 is capable of inducing compacted chromatin reformation through the removal of acetyl groups, and is highly important for maintaining chromatin stability (Fritah et al, 2009;Lou et al, 2009;Raynes et al, 2013a).…”

Tumor-derived hepatocyte growth factor is associated with poor prognosis of patients with glioma and influences the chemosensitivity of glioma cell line to cisplatin in vitro

“…Although various molecular markers involved in chemotherapy resistance have been investigated, their direct roles in the chemosensitivity and prognostic value of gliomas, except MGMT (O 6 -methylguanine DNA methyltransferase), remain controversial [20]. Recently, a study has also exhibited that inhibition of c-Met enhanced the chemosensitivity of glioma cell lines to cisplatin, but no clear molecular mechanism involvement has emerged [21]. The relationship, if any, between HGF and chemoresistance in gliomas needs to be verified.…”