Mechanisms of autophagy and apoptosis: Recent developments in breast cancer cells

Abstract

Autophagy, the pathway whereby cell components are degraded by lysosomes, is involved in the cell response to environmental stresses, such as nutrient deprivation, hypoxia or exposition to chemotherapeutic agents. Under these conditions, which are reminiscent of certain phases of tumor development, autophagy either promotes cell survival or induces cell death. This strengthens the possibility that autophagy could be an important target in cancer therapy, as has been proposed. Here, we describe the regulation of survival and death by autophagy and apoptosis, especially in cultured breast cancer cells. In particular, we discuss whether autophagy represents an apoptosis-independent process and/or if they share common pathways. We believe that understanding in detail the molecular mechanisms that underlie the relationships between autophagy and apoptosis in breast cancer cells could improve the available treatments for this disease. AUTOPHAGYAutophagy is the process whereby organelles and other cell components are degraded by lysosomes. There are various types of autophagy, including macroautophagy, microautophagy and chaperone-mediated autophagy [1] . Macroautophagy, hereafter called autophagy, is the most important form of autophagy and involves the formation of double-membrane vacuoles, named autophagosomes, containing cytosol and organelles. Autophagosomes then fuse with endosomes and lysosomes to form autolysosomes (Figure 1), which undergo a gradual acidification, by a proton pump, and degradation, by hydrolytic enzymes, of their content [2] . Autophagosome formation is a complex mechanism in which different autophagy-related (Atg) proteins participate, including Beclin 1 and LC3 (Atg6 and Atg8 in yeast, respectively), and which also requires the cell cytoskeleton [1,3,4] . Autophagy occurs at basal levels in almost all cells, and its main function is the degradation of cell components, including long-lived proteins, protein aggregates and organelles produced in excess, aged, damaged and potentially dangerous or no longer needed [5,6] .

Inhibiting autophagy increases epirubicin's cytotoxicity in breast cancer cells

“…Some studies suggest that autophagy can promote cell death in breast cancer with a sufficient stimulus or when apoptosis is inhibited. In contrast, autophagy may be triggered by cytotoxic agents to prevent cell death and inhibitors of autophagy enhance cytotoxicity and increase cell death . Our former study confirmed that blocking EPI‐induced autophagy increased caspase‐9‐dependent intrinsic apoptosis and promoted cell death .…”

Honokiol exhibits enhanced antitumor effects with chloroquine by inducing cell death and inhibiting autophagy in human non-small cell lung cancer cells

“…Stress conditions induce cancer cells to autophagy and it enables cancer cells to survive by providing biosynthetic precursors, maintaining energy production, and clearing injured cell components (22). Clearly, autophagy plays an important role in tumor cell survival under extreme stress, thus inhibition of autophagy may become a novel therapeutic strategy for cancer treatment (23,24).…”

The Anticancer Agent Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Prosurvival Autophagy by Two Mechanisms

“…The human MCF7 breast cancer cell line was used initially because autophagy has been well characterized in this cell line (45). In these investigations, Dp44mT was used at low concentrations of up to 5 M because of its high membrane permeability and marked iron chelation efficacy (20).…”