Autophagy: novel applications of nonsteroidal anti-inflammatory drugs for primary cancer

Abstract

In eukaryotic cells, autophagy is a process associated with programmed cell death. During this process, cytoplasmic proteins and organelles are engulfed by double-membrane autophagosomes, which then fuse with lysosomes to form autolysosomes. These autolysosomes then degrade their contents to recycle the cellular components. Autophagy has been implicated in a wide variety of physiological and pathological processes that are closely related to tumorigenesis. In recent years, an increasing number of studies have indicated that nonsteroidal anti-inflammatory drugs, such as celecoxib, meloxicam, sulindac, aspirin, sildenafil, rofecoxib, and sodium salicylate, have diverse effects in cancer that are mediated by the autophagy pathway. These nonsteroidal anti-inflammatory drugs can modulate tumor autophagy through the PI3K/Akt/mTOR, MAPK/ERK1/2, P53/DRAM, AMPK/mTOR, Bip/GRP78, CHOP/ GADD153, and HGF/MET signaling pathways and inhibit lysosome function, leading to p53-dependent G1 cell-cycle arrest. In this review, we summarize the research progress in autophagy induced by nonsteroidal anti-inflammatory drugs and the molecular mechanisms of autophagy in cancer cells to provide a reference for the potential benefits of nonsteroidal anti-inflammatory drugs in cancer chemotherapy.

Keywords: Autophagy; nonsteroidal anti-inflammatory drugs; programmed cell death.

Figure 1

NSAIDs significantly induce autophagy. The most important pathway is mTOR signaling pathway, including PI3K/AKT and AMPK/mTOR. Similarly, NSAIDs also regulate directly the target genes, such as LC3B, P62, P53, Atg5, Atg12, and HIF‐1, the latest Discovered.

Figure 2

Among the initial steps of vesicle nucleation is the activation of mammalian Vps34, a class III phosphatidylinositol 3‐kinase (PI3K), to generate phosphatidylinositol‐3‐phosphate. Vps34 activation depends on the formation of a multiprotein complex of beclin‐1, UVRAG, and BH393.

Figure 3

Upstream cell signaling pathway of autophagy. Fuchsia: growth factor activates PI3K/AKT/mTOR signaling pathway; dark green: starvation and endoplasmic reticulum stress promote autophagy through AMPK/CaMKK signaling pathway; dark yellow: P53/DRAM signaling pathway; pale green: Ras signaling pathway can not only promote autophagy but also inhibit autophagy; and light blue: various NSAIDs modulate different signaling pathways to promote autophagy.

Figure 4

Interaction between different types of programmed cell death and NSAIDs. At late stage and longer term, NSAIDs (e.g., celecoxib, meloxicam, and aspirin) switch from autophagy to apoptosis. At early period and shorter term, they switch from apoptosis to autophagy.