Stress signaling in cancer

Abstract

The human body is continuously exposed to a wide variety of physical, chemical, and biological stress stimuli from both the external and internal environments. In order to adapt to or resist stress, cells are equipped with multiple signaling systems, which elicit a wide range of stress responses. Stress signaling also operates to eliminate cells with severe stress-induced damage through the induction of apoptosis. Once stress signaling is compromised in certain adverse conditions, however, cells exhibit aberrant responses to stress, which can eventually cause various diseases including cancer. In the present review, the authors focus on the current understanding of the critical linkage between stress signaling and cancer.

Figure 1

Stress and cancer: Various stresses are involved in each step of tumorigenesis.

Figure 2

Mitogen‐activated protein kinase (MAPK) cascade. MAPK cascade is an intracellular signaling system consisted of three classes of protein kinases; MAPKKK, MAPKK and MAPK. MAPKKK activated by various extrinsic and intrinsic stimuli, phosphorylate and thereby activate MAPKK, and in turn MAPKK phosphorylate and activate MAPK. The activated MAPK induces a variety of cellular responses such as gene expression through phosphorylating transcription factors. In mammals, three major MAPK cascades converge on extracellular signal‐regulated kinases (ERK), c‐Jun NH₂‐terminal kinases (JNK), and p38 MAPK. Whereas the ERK pathway is generally involved in the control of cell proliferation and differentiation by growth factors, etc., the JNK/p38 pathway is activated by various stress stimuli and leads to diverse stress responses including apoptosis, survival and differentiation, etc.

Figure 3

The thioredoxin (Trx)–apoptosis signal‐regulating kinase (ASK)1 system. ASK1 is activated by reactive oxygen species (ROS) via the ASK1–Trx system. Trx binds to ASK1 and keeps it inactivated in steady‐state ASK1 signalosome. On dissociation of Trx oxidized by ROS, ASK1 signalosome shifts to activated‐state complex by recruiting tumor necrosis factor receptor‐associated factor (TRAF)2 and TRAF6 reciprocally.

Figure 4

The thioredoxin (Trx)–apoptosis signal‐regulating kinase (ASK)1 system commonly used in various stimuli: ASK1 is also activated in lipopolysaccharide (LPS)–Toll‐like receptors (TLR)4–tumor necrosis factor (TNF) receptor‐associated factor (TRAF)6 axis and TNF‐α–TNFR1–TRAF2 axis in a reactive oxygen species (ROS)‐dependent manner.

Figure 5

The nuclear factor‐κB (NF‐κB) pathway: Activation of the NF‐κB master transcriptional factor is thought to occur via either a classical pathway or an alternative pathway. The classical pathway is activated by a variety of inflammatory signals such as tumor necrosis factor (TNF)‐α, interleukin (IL)‐1, and lipopolysaccharide (LPS). The signal triggers activation of the IκB kinase (IKK) complex, which includes IKK‐α, IKK‐β and NEMO. This leads to phosphorylation, poly ubiquitination, and eventually degradation of the inhibitor of NF‐κB (IκB) protein. Degradation of IκB releases p50–p65 NF‐κB dimmers to activate κB site‐gene transcription. The alternative pathway is triggered by certain members of the TNF superfamily. In this pathway, signals are mediated by homodimers of IKK‐α and results in the subsequent liberation of p52/RelB NF‐κB dimers into the nucleus.