Apoptotic signaling pathways in lung cancer.

Tumor cells may respond to chemoor radiotherapy by activation of several cellular signaling cascades that influence cell survival and cell death, including activation of cell cycle arrest, senescence or triggering of several cell death types (i.e., mitotic catastrophe, necrosis, or apoptosis). 1,2 However, tumor cells derived from solid tumors are often refractory to therapy or develop resistance during the treatment course. This is illustrated by non-small cell lung cancer (NSCLC), which shows a high degree of intrinsic resistance, and by small cell lung cancer (SCLC), which often develops resistance to treatment during the course of disease.3 In part, defective apoptotic signaling may contribute to chemo-resistance and radiotherapy resistance.1 However, it is also likely that other cell death modes (e.g., necrosis, autophagy, and mitotic catastrophe) and premature senescence are of equal importance for efficient tumor cell death in response to chemoand radiotherapy.2 In this article, we give a brief overview of the main apoptotic signaling pathways and their deregulation in lung cancer (LC), and we provide some examples of apoptosis-based therapies. Apoptosis is distinguished by some morphological characteristics (i.e., plasma membrane blebbing, cell shrinkage, condensation/fragmentation of the chromatin, and disintegration of the cell into apoptotic bodies). All these characteristics are effects of selective proteolysis of proteins involved in cell signaling, DNA repair, or structural maintenance of DNA integrity, carried out by caspases, a group of cystein-aspartate enzymes.4 Caspases are classified as initiator caspases (caspase-2, -8, -9, and -10 within human cells), which, upon activation, cleave and activate the second group, the effector caspases (mainly caspase-3, -6, and -7 within human cells), then perform selective proteolysis.4 Caspases are activated either by death receptor (DR) activation (extrinsic) or via mitochondrial release of apoptogenic proteins (e.g., cytochrome c, smac/DIABLO, and HtrA2/ Omi) (intrinsic) (Figure 1). The signals propagated by the intrinsic pathway may also be generated in cell nuclei or lysosomes or within the endoplasmatic reticulum (Fig. 1). 5–7 In the extrinsic caspase activation pathway, TNF superfamily ligands bind to DRs, causing oligomerization of DRs and recruitment of adaptor proteins via a death domain. In turn, adaptor proteins bind pro-caspase-8 via a death effector domain (DED) allowing pro-caspase-8 to be activated, an event that is critically dependent on the adaptor recruitment domain in the pro-caspase-8.8 Active caspase-8 then either activates pro-caspase-3 directly or amplifies the signal through Bid-cleavage (Figure 1). 9 In the intrinsic pathway, apoptotic signals trigger increased mitochondrial outer membrane permeability (MOMP), followed by selective release of apoptogenic proteins from the mitochondrial inter membrane space to the cytosol (e.g., cytochrome c, Smac/ DIABLO, and HtrA2/omi), all which promote caspase activation (Fig. 1). 9 Cytosolic cytochrome c forms a complex with apoptosis protease-activating factor 1 (Apaf-1) and dATP (i.e., the apoptosome), in which the dimerization of procaspase-9 occurs, allowing its activation into caspase-9. This is followed by pro-caspase-3 activation.8 For these to efficiently result in apoptotic propagation, the concomitant alleviation of the caspase-blocking effect of inhibitor of apoptosis proteins (IAPs) is required. Hence, the release of Smac/ DIABLO and HtrA2/omi, both which block IAPs and both which are released as a consequence of increased MOMP, leads to increased caspase-3 activity.9 In part, MOMP is controlled by Bcl-2 family proteins, and the anti-apoptotic members Bcl-xL and Bcl-2 both inhibit MOMP. Accordingly, pro-apoptotic members such as Bak or Bax, both which are activated by some BH3-only proteins (Bid, Bim, Bad, PUMA, and NOXA), can promote MOMP.10 An important regulator of mitochondria-mediated signaling is the tumor suppressor p53. Thus, p53 may induce expression of pro-apoptotic proteins (e.g., Bax, PUMA, Apaf-1) and/or repress anti-apoptotic proteins, including Bcl-2, in response to DNA damage.11 In addition, p53 can re-localize to cytosol and in the same way as BH3-only proteins trigger Bak and/or Bax activation.12,13