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    • In vitro studies using shRNAs to target autophagy regulators

    2018-11-14

    In vitro studies using shRNAs to target >100 autophagy regulators identified a number of breast cancer cell lines that are dependent upon functional autophagy for growth even in the absence of stress (Maycotte et al., 2014). Importantly however, some tumor cell lines were barely affected by autophagy gene knockdown indicating that tumor KN-93 hydrochloride differ greatly in their dependence on autophagy. This work followed studies suggesting that cancer cell lines with mutant RAS genes are “autophagy addicted” (Guo et al., 2011) and some tumor types, e.g. pancreas cancer, which transcriptionally induces high levels of autophagy (Perera et al., 2015), are highly dependent on autophagy (Yang et al., 2011). However, RAS mutation alone does not determine sensitivity to autophagy inhibition in vitro (Morgan et al., 2014) highlighting the need for more rigorous studies to identify which tumor cells are, or are not, autophagy-dependent. Similarly, in vivo studies have indicated the necessity of Atg5 or Atg7 in KRAS- or BRAF-driven tumor models (Karsli-Uzunbas et al., 2014; Rao et al., 2014; Rosenfeldt et al., 2013; Yang et al., 2014; Guo et al., 2013; Strohecker et al., 2013; Xie et al., 2015). A requirement for autophagy to maintain tumors in vivo has also been demonstrated for cancers driven by PTEN loss (Santanam et al., 2016). Moreover, additional autophagy regulators such as FIP200, have been shown to maintain tumor growth due to autophagy and not other functions of the protein (Chen et al., 2016). One caveat for many of the mouse studies is that deletion of the Atg gene occurs simultaneously with activation of the oncogenic driver and occurs only in the tumor cells. These experiments do not adequately model what autophagy inhibition would be like in the clinic. A patient would likely only be treated after they had a full-blown cancer with an autophagy inhibitor that cannot discriminate between autophagy in the cancer cells and autophagy in the rest of the body. This has been modeled in KRAS-driven lung cancer, where tumors were allowed to develop before systemic loss of the Atg7 gene was achieved (Karsli-Uzunbas et al., 2014). Complete, irreversible inhibition of autophagy by Atg7 deletion in adult mice caused death by bacterial infection or, after several weeks, neurodegeneration and the animals displayed defects in glucose homeostasis and extreme sensitivity to starvation. However, these results also indicate a therapeutic window where the tumor can be eradicated without wholesale toxicity when autophagy is inhibited. The existence of such a therapeutic window– a given dose and/or length of treatment time that can be effective in inhibiting tumor growth without overt toxicity, provides an opportunity for therapeutic inhibition. In the clinic we would likely never have a drug that is as good at inhibiting autophagy as complete knockout of an ATG gene. Moreover, autophagy inhibition with a drug could be reversed by removing the drug, thus this work tells us that even a “perfect” autophagy inhibitor might not be so toxic that it couldn\'t be used in cancer therapy. As with its tumor suppressing roles, the mechanisms by which autophagy supports tumor growth are poorly understood. Autophagy has been implicated in the pro-tumorigenic processes of glycolysis, oxidative metabolism, cell proliferation and anchorage-independent growth (Lock et al., 2011; Vander Heiden et al., 2009). In addition autophagy is involved in metastasis (Kenific et al., 2010). For example, it is important in tumor cell invasion and migration, and metastasis in vivo due to autophagy induced focal adhesion disassembly (Kenific et al., 2016; Sharifi et al., 2016) and autophagy-regulated cytokine secretion (Lock et al., 2014). Autophagy deficiency in cancer cells results in multiple metabolic problems and the accumulation of defective mitochondria (Guo et al., 2016). Additionally autophagy in stromal cells can promote tumor cell metabolism by feeding amino acids (specifically alanine) to the tumor cells (Sousa et al., 2016). It is likely that a combination of metabolic effects and other cellular functions such as cytokine secretion contribute to autophagy\'s ability to promote tumor growth and progression and thus explain how, for some tumors, autophagy inhibition alone can have profound anti-cancer effects.