Autophagy as a cytoprotective mechanism in esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is amongst the most aggressive human malignancies, representing a significant health burden worldwide. Autophagy is an evolutionarily conserved catabolic process that degrades and recycles damaged organelles and misfolded proteins to maintain cellular homeostasis. Alterations in autophagy are associated with cancer pathogenesis, including ESCC; however, the functional role of autophagy in ESCC remains elusive. Here, we discuss the clinical relevance of autophagy effectors in ESCC and review current knowledge regarding the molecular mechanisms through which autophagy contributes to ESCC. We highlight the cytoprotective role of autophagy in ESCC and discuss autophagy inhibitors as novel experimental therapeutics to potentiate the effects of anti-cancer therapies and/or to overcome therapeutic resistance in ESCC.

Figure 1. Autophagy is a tumor promoting factor in ESCC

Autophagy activation has been documented in esophageal squamous cell carcinoma (ESCC) cells in response to both endogenous and exogenous stimuli. Metastasis-associated colon cancer 1 (MACC1)-mediated induction of autophagy promotes ESSC cell proliferation, migration and invasion. Transforming growth factor (TGF)-β in the tumor microenvironment induces autophagy to promote expansion of CD44^High cancer stem cells (CSCs). Autophagy also promotes expansion of OV6+ CSCs via Wnt/β-catenin signaling; however, the mechanisms regulating autophagy activation in this context remain to be determined. Activation of autophagy by chemo- and radiotherapy as well as various experimental ESCC therapeutics induce autophagy that has largely been shown to act in a cytoprotective fashion to limit therapy-induced cell death and promote therapy resistance.

Figure 2. Strategies for pharmacological autophagy inhibition

Chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) act at the lysosome to prevent autophagic vesicle (AV) clearance. Clinical trials using CQ or HCQ have been executed for various cancer types with varying results in terms of both patient outcomes and effects on autophagy in tumor tissues. Lys05, a dimeric analog of CQ, exhibits increased potency with regard to single-agent antitumor activity and autophagy inhibition as compared to HCQ in preclinical models; however, the clinical utility of this agent has yet to be established. Inhibitors of more proximal steps in autophagy have been utilized in preclinical studies, including those targeting unc-51-like kinase 1 (ULK1) and the class III phosphoinositide 3-kinase VPS34, two positive effectors of AV nucleation, and the cysteine protease ATG4B, a mediator of AV elongation. As these agents are further developed, it will be of great interest to determine their effects on human tumors either alone or in combination with established therapeutic modalities. This is particularly true of esophageal squamous cell carcinoma in which current data supports a tumor promoting role for autophagy and therapeutic resistance represents as substantial clinical challenge.