Role of Autophagy and Apoptosis in Non-Small-Cell Lung Cancer

Abstract

Non-small-cell lung cancer (NSCLC) constitutes 85% of all lung cancers, and is the leading cause of cancer-related death worldwide. The poor prognosis and resistance to both radiation and chemotherapy warrant further investigation into the molecular mechanisms of NSCLC and the development of new, more efficacious therapeutics. The processes of autophagy and apoptosis, which induce degradation of proteins and organelles or cell death upon cellular stress, are crucial in the pathophysiology of NSCLC. The close interplay between autophagy and apoptosis through shared signaling pathways complicates our understanding of how NSCLC pathophysiology is regulated. The apoptotic effect of autophagy is controversial as both inhibitory and stimulatory effects have been reported in NSCLC. In addition, crosstalk of proteins regulating both autophagy and apoptosis exists. Here, we review the recent advances of the relationship between autophagy and apoptosis in NSCLC, aiming to provide few insights into the discovery of novel pathogenic factors and the development of new cancer therapeutics.

Keywords: apoptosis; autophagy; crosstalk; endoplasmic reticulum (ER) stress; mammalian target of rapamycin (mTOR); non-small-cell lung cancer (NSCLC); p53.

Figure 1

p53 promotes apoptosis and inhibits autophagy. Nuclear p53 induces autophagy and the transcription of multiple apoptotic genes that function in both extrinsic and intrinsic apoptosis pathway. Cytoplasmic pools of p53 directly or indirectly trigger MOMP and lead to apoptosis. In addition, cytoplasmic p53 inhibits autophagy by FIP200 or the AMPK/mTOR pathway.

Figure 2

Overview of mammalian target of rapamycin (mTOR) pathway. The crosstalk of different pathways including (PI3K)/ (PI3K/AKT)/mTOR (phosphoinositide-3-kinase-protein/kinase B/mTOR), LKB1/AMPK/mTOR (serine/threonine kinase 11/ AMP-activated protein kinase/mTOR) and Raf/MEK/mTOR (rapidly accelerated fibrosarcoma/ mitogen-activated protein kinase kinase/mTOR) and their regulation of autophagy. Aberrant genes associated with NSCLC are marked in white. Hexagons and ovals are representative of lipids and proteins, respectively. Arrows indicate stimulation and T-bars indicate inhibition. PtdIns(3,4,5)P₃ (PIP3) can activate AKT directly or recruit 3-phosphoinositide-dependent protein kinase-1 (PDK1) to phosphorylate AKT.

Figure 3

ER stress mediates apoptosis and autophagy.