Role of the p38 MAPK pathway in cisplatin-based therapy

Abstract

p38 MAPK has been implicated in the response to cancer therapy. To determine whether the activation of p38 MAPK could be specific to cancer therapy, we investigated the activation of p38 MAPK in response to several chemotherapeutic agents, such as cisplatin, doxorubicin and taxol in several human cell lines. Activation of p38 MAPK was measured after exposure to several chemotherapeutic agents, using specific phosphoantibodies. Only cisplatin was able to activate p38 MAPK in all the cell lines tested. Furthermore, other platinum compounds such as transplatin and platinum (IV) chloride can induce activation of p38 MAPK. The kinetics of this activation is a key event in the biological role of p38 MAPK in response to cisplatin, as we conclude from the differences observed after treatment with transplatin and cisplatin. The p38 MAPK activation is independent of the origin or genetic alterations of the cell lines and seems to be mediated through both upstream activators MKK6 and MKK3. Although the isoforms a/b are mainly activated, we also demonstrated that other members of the p38 MAPK family were susceptible to activation by cisplatin when they were overexpressed in 293 T. Finally, pretreatment with specific inhibitors (SB 203580 and SKF 86002) induces a resistant phenotype in response to cisplatin. Furthermore, low activation of this SAPK pathway correlates with a resistant phenotype as demonstrated in our experimental model of head and neck cancer. Therefore, we conclude that the p38 MAPK pathway is a specific target for cisplatin-based therapy with clinical implications.

Indirubin-3′-monoxime inhibits autophosphorylation of FGFR1 and stimulates ERK1/2 activity via p38 MAPK

“…It is also known that p38 MAPK can be activated during different types of chemotherapy. Genotoxic drugs like cisplatin (Losa et al, 2003) as well as kinase inhibitors or ultraviolet and g-irradiation (Brancho et al, 2003;Losa et al, 2003) are recognized as agents able to stimulate p38 MAPK as well as JNK pathways (Bulavin et al, 1999;Sanchez-Prieto et al, 2000;Yu et al, 2000). It was reported that stimulation of p38 MAPK and JNK activity is crucial for cisplatin-induced apoptosis (Benhar et al, 2001), but specific inhibition of JNK or p38 MAPK suppresses the drug-induced cell death process (Tibbles and Woodgett, 1999).…”

Epicatechin protects the auditory organ by attenuating cisplatin-induced ototoxicity through inhibition of ERK

“…In A2780 ovarian carcinoma cells, ERK was weakly activated by cisplatin, whereas JNK was more significantly activated (Cui et al, 2000). In HaCaT cells, cisplatin did not activate ERK but did activate JNK and p38 MAPK (Losa et al, 2003). Chen et al reported that exogenous cannabinoids produced cellular protection by inactivation of JNK or p38 MAPK (Chen et al, 2005).…”

Regulation of glioblastoma cell invasion by PKCι and RhoB

“…To determine whether the effects of PKCi on RhoB involved p38MAP kinase, U87MG cells depleted of PKCi were treated with the p38MAP kinase inhibitor SKF86002, which is active against all four p38MAP kinase members (Losa et al, 2003). SKF86002 had no effect on RhoB levels in U87MG cells, and did not affect the increase in RhoB with PKCi depletion (Figures 3c and d).…”