p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents

Abstract

The Mitogen Activated Protein Kinase (MAPK) signaling plays a critical role in the outcome and the sensitivity to anticancer therapies. Activated MAPK can transmit extracellular signals to regulate cell growth, proliferation, differentiation, migration, apoptosis and so on. Apoptosis as well as macroautophagy (hereafter referred to as autophagy) can be induced by extracellular stimuli such the treatment of chemotherapeutic agents, resulting in different cell response to these drugs. However, the molecular mechanisms mediating these two cellular processes remain largely unknown. Recently, several studies provide new insights into p38 and JNK MAPK pathways function in the control of the balance of autophagy and apoptosis in response to genotoxic stress. Our increased understanding of the role of p38 and JNK MAPK pathways in regulating the balance of autophagy and apoptosis will hopefully provide prospective strategies for cancer therapy.

Introduction

The Mitogen Activated Protein Kinase (MAPK) pathway plays a key role in the development and progression of cancer [1]. The classical MAPK pathway consists of the extracellular-signal-regulated kinase (ERK), the c-jun N-terminal kinase or stress-activated protein kinase (JNK or SAPK); and MAPK14 [2]. So far, there are six distinct groups of MAPK have been involved in mammals—ERK1/2, ERK3/4, ERK5, ERK7/8, JNK1/2/3 and the p38 isoforms α/β/γ(ERK6)/δ [3], [4], [5]. MAPK pathway can be activated by extracellular stimuli, such as Gi-Coupled Receptor (GPCR), ultraviolet irradiation, genotoxic agents and oxidative stress, but are also activated following growth factors, inflammatory and cytokine stimulation. Once activated, MAPK exerts an important role in converting extracellular stimuli into a wide range of cellular responses, including proliferation, differentiation, senescence and so on [6], [7], [8]. The role of MAPK in cancer is as pleiotropic as cancer itself and stress-activated MAPK, such as p38 MAPK and JNK, seem to widely vary in different tumors, but are important for the outcome and the sensitivity to drug therapy (see Fig. 1).

For several decades, apoptosis has been considered as the principal mechanism of programmed cell death in mammalian cells. Traditional cancer therapy is also mainly targeting on enhancing cell apoptosis. However, accumulating evidence suggests that the effects of anticancer therapies are not confined to apoptosis but also involve autophagy. Autophagy is an evolutionarily conserved catabolic process of self-degradation of organelles and cytosolic macromolecules [9]. Consistent with apoptosis, autophagy plays an important role in the cell death, normal physiology, and cellular homeostasis. But, the difference is that the role of autophagy in regulating cancer cell death remains controversial. Autophagy itself fulfils a dual role, having pro-death or pro-survival role depending on the cell type and strength of specific stimuli [10], [11], [12]. The autophagy-dependent non-apoptotic cell death is defined as type II programmed cell death. Autophagy and apoptosis are two distinct processes which play seemingly opposite biological roles in response to genotoxic or pharmacological stresses. The crosstalk between autophagy and apoptosis is quite complicated, and has not been well elucidated. Both autophagy and apoptosis may be triggered by common upstream signals, resulting in the activation of combined autophagy and apoptosis. Under certain conditions, they may be also mutually exclusive. Recent work has suggested that MAPK, especially p38 MAPK and JNK, play a key role in crosstalk between autophagy and apoptosis induced by genotoxic stress. However, it remains an ongoing issue how the cells ‘decide’ to respond to similar stimuli by preferentially undergoing apoptosis or autophagy. In this review we will describe the recent progress made in determining the role of p38 and JNK MAPK pathways in regulating the balance of autophagy and apoptosis, and discuss how this relates to the resistance to anticancer therapies.