Modulation of the p38 MAPK (mitogen-activated protein kinase) pathway through Bcr/Abl: implications in the cellular response to Ara-C

Abstract

The chimaeric protein Bcr/Abl, the hallmark of chronic myeloid leukaemia, has been connected with several signalling pathways, such as those involving protein kinase B/Akt, JNK (c-Jun N-terminal kinase) or ERKs (extracellular-signal-regulated kinases) 1 and 2. However, no data about the p38 MAPK (mitogen-activated protein kinase) have been reported. Here, we present evidence showing that Bcr/Abl is able to modulate this signalling pathway. Transient transfection experiments indicated that overexpression of Bcr/Abl in 293T cells is able to activate p38 MAPK or induce p73 stabilization, suggesting that c-Abl and Bcr/Abl share some biological substrates. Interestingly, the control exerted by Bcr/Abl on the p38 MAPK pathway was not only mediated by the tyrosine kinase activity of Bcr/Abl, as the use of STI571 demonstrated. In fact, Bcr alone was able to induce p38 MAPK activation specifically through MKK3 (MAP kinase kinase 3). Supporting these observations, chronic myeloid leukaemia-derived K562 cells or BaF 3 cells stably transfected with Bcr/Abl showed higher levels of phosphorylated p38 MAPK compared with Bcr/Abl-negative cells. While Bcr/Abl-negative cells activated p38 MAPK in response to Ara-C (1-beta-D-arabinofuranosylcytosine), Bcr/Abl-positive cells were unable to activate p38 MAPK, suggesting that the p38 MAPK pathway is not sensitive to Abl-dependent stimuli in Bcr/Abl-positive cells. Our results demonstrate that the involvement of Bcr/Abl in the p38 MAPK pathway is a key mechanism for explaining resistance to Ara-C, and could provide a clue for new therapeutic approaches based on the use of specific Abl inhibitors.

RETRACTED ARTICLE: P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance

“…The first one is the critical role of the p38MAPK signaling pathway in response to 5-FU. Therefore, 5-FU can be included in the growing list of antitumor agents such as cisplatin, ara-c or radiotherapy (Losa et al, 2003;Sanchez-Arevalo, et al, 2005;Lafarga et al, 2009), in which p38MAPK signaling pathway is a major determinant of the therapeutic effects. Previous reports indicated an activation of p38MAPK by 5-FU, but no relation to resistance was established (Elsea et al, 2008;Zhao et al, 2008).…”

“…Thus, the p38MAPK signaling pathway has been shown to be a major mediator in the response and resistance to several antitumor agents such as cisplatin, ara-c or gemcitabine (Losa et al, 2003;Habiro et al, 2004;Koizumi et al, 2005;Sanchez-Arevalo et al, 2005;Galan-Moya et al, 2008). Interestingly, ara-c and gemcitabine are members of the same family of 5-FU (anti-metabolites), but no relationship between 5-FU resistance and p38MAPK has been reported.…”

Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression

“…4,5 A major cellular serine/threonine phosphatase working to down-regulate activation of these pathways is the tumor suppressor protein phosphatase 2A (PP2A). 6 In CML cells, PP2A is a key target of BCR-ABL1 signaling; this protein becomes inactivated in these cells because BCR-ABL1 stimulates prevention of its auto-dephosphorylation at tyrosine 307 .…”

MicroRNAs mediated regulation of MAPK signaling pathways in chronic myeloid leukemia

“…Gene product of BCR-ABL exerts a constitutive tyrosine kinase activity crucial for the function of several signaling pathways involved in various malignancies, including CML [12]. Accordingly, a modifications in most of the members of the MAPKs have been observed due to BCR/ABL transformation and have been found associated with cell survival or drug resistance [8, 13, 14]. Taking into consideration the importance of MAPK in CML, specific inhibitors for BCR-ABL tyrosine kinase activity have been designed and are being developed for treating CML [15].…”