# Cellular Self-Digestion and Persistence in Bacteria
## 6 Importance of Autophagy in Drug Tolerance
Cancer persisters can escape cell death pathways (e.g., apoptosis) by inactivating their cell-proliferation signaling pathways during treatment. In fact, many targeted therapeutics may induce cell dormancy by directly inhibiting cell-proliferation signaling pathways, whereas chemotherapics may indirectly stimulate growth arrest by activating stress signaling pathways [274; 275; 276]. Critically, the mechanisms associated with cell growth arrest may be mediated by the same signaling pathways that are involved in autophagy [273]. The degree of stress (e.g., starvation) that a cell is under can determine if autophagy will be used as a means for survival [263] or programmed cell death [278]. However, autophagy is not only a defense mechanism for starvation, but a necessary function for molecular recycling and maintaining the homeostasis of non-starved cells [263]. Knockout of ATGs has been shown to cause severe developmental problems in mice, including abnormalities at the cellular level [279], obesity [280], lung dysfunction [281], tumorigenesis [282; 283], and death [283]. Critically, dependence of tumor cell survival and growth on basal autophagy has also been demonstrated via ATG knockout [284], and numerous observations support a key role for autophagy in cancer growth and survival. In one instance, it was shown that deletion of ATG7 leads to metabolic and proliferative problems in cancer, causing cancer cells to become more sensitive to starvation and more dependent on glutamine [285]. RAS-mutated cancers were also found to exhibit upregulated autophagy, leading to sustained TCA cycle metabolism [286], increased levels of glycolysis [287], and enhanced tumorigenesis [286; 288]. In addition to providing support for cancer growth and survival under stress, autophagy can help cancer cells resist treatment. Increasing levels of autophagic flux have been correlated with higher cancer cell survival rates and shortened patient survival times in melanoma [289]. The specific mechanisms that mediate this phenomenon have not been fully elucidated; however, autophagy appears to play various protective roles in cancer, depending on the cancer type and the treatment method. For example, in BRAF-mutated cancers, BRAF inhibition leads to endoplasmic reticulum (ER) stress, which subsequently increases autophagic activity, protecting the cells from apoptosis and maintaining mitochondrial activity [290]. Autophagy also makes mTOR-mutated cancer cells tolerant to mTOR inhibitors by eliminating receptor-interacting protein kinases (RIPKs), which promote necroptosis when autophagy is inhibited [291]. Overall, both autophagy and self-digestion seem to be evolutionarily conserved mechanisms that allow organisms to survive undesirable environmental conditions. Both processes can be activated in response to extracellular stress conditions such as nutrient deprivation; maintain cellular energy homeostasis; may use similar degradative enzymes (such as Lon); and can lead to growth arrest, and therefore tolerance to both antibiotics (for bacteria) and chemotherapeutics (for cancer cells).