Targeting autophagy in cancer

Abstract

Preface Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation allowing basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has caused therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. Here we suggest a way forward for effective targeting of autophagy by understanding the context-dependent roles of autophagy and capitalizing on modern approaches to clinical trial design.

Differences of basic and induced autophagic activity between K562 and K562/ADM cells

“…Abnormal basal autophagy can lead to various human diseases including cancer, neurodegenerative disorders, autoimmunity disease and inflammation (12)(13)(14)(15). Autophagy can be induced in response to several stressors including: nutrient deprivation, chemotherapeutics, hypoxia, pathogen infection and endoplasmic reticulum stress (16)(17)(18).…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…According to the contents of engulfed substances to be degraded, such as misfolded proteins, redundant peroxisomes, pathogenic organisms, and dysfunctional mitochondria, the autophagic machinery has been subdivided into four subtypes, namely aggrephagy, perophagy, xenophagy, and mitophagy, respectively (Cordani, Butera, Pacchiana, & Donadelli, 2017; Guo, Cheng et al., 2017; Kaur & Debnath, 2015). The autophagic pathway utilizes a well‐orchestrated cascade of forming and targeting autophagosomes carried out by autophagy‐related proteins (ATGs) (Levy et al., 2017). Under physiological conditions, the autophagic cascade is initiated following the activation of AMPK by energy deprivation, which consequently exerts inhibitory effects on mTORC1 (mTOR complex 1) (Cadwell, 2016; Cheng, Zhang, Ji, Tao, & Guo, 2016).…”

“…The membrane elongation and cargo recognition process require the involvement of this trimeric complex, as well as an ubiquitin‐like protein LC3 (microtubule‐associated protein 1 light chain 3). An autolysosome is then formed by the fusion of autophagosome and the lysosome, leading to the degradation of the cargo within the autophagosome (Guo, Cheng et al., 2017; Levy et al., 2017). …”

“…Trehalose, a disaccharide that inhibits glucose transporters, leads to the activation of AMPK and autophagy, attenuating the proteotoxic effects in affected neurons (DeBosch, Heitmeier, Mayer, Higgins, & Crowley, 2016; Menzies et al., 2017). Metformin, another well‐known AMPK activator initially approved to treat patients with diabetes, could also restore the machinery of autophagy and exhibit anti‐AD effects (Levy et al., 2017). In addition, GTM‐1, a novel small molecule, can ameliorate neurotoxicity triggered by oligomeric Aβ accumulation through an mTOR‐independent activation of autophagy (Guo, Liu, Cai, & Le, 2017) (Table 4).…”

“…On the other hand, a well‐balanced degradation of excessive or malformed proteins is also important to maintain protein homeostasis. Two major pathways regulating protein removal include autophagy and the ubiquitin–proteasome system (UPS) to promote the physiological degradation of marked proteins, either through a lysosome‐dependent or ubiquitination‐dependent manner (Leithe, 2016; Levy, Towers & Thorburn, 2017). Any aberrant event on these pathways can lead to protein dysregulation and result in pathological onset.…”