Abstract
Early acquisition of sorafenib resistance is responsible for the dismal prognosis of advanced hepatocarcinoma (HCC). Autophagy, a catabolic process involved in liver homeostasis, has been associated with chemosensitivity modulation. Forkhead box O3 (FOXO3) is a transcription factor linked to HCC pathogenesis whose role on autophagy-related sorafenib resistance remains controversial. Here, we unraveled the linkage between autophagy and sorafenib resistance in HCC, focusing on the implication of FOXO3 and its potential modulation by regorafenib. We worked with two HepG2-derived sorafenib-resistant HCC in vitro models (HepG2S1 and HepG2S3) and checked HCC patient data from the UALCAN database. Resistant cells displayed an enhanced basal autophagic flux compared to HepG2, showing higher autophagolysosome content and autophagy markers levels. Pharmacological inhibition of autophagy boosted HepG2S1 and HepG2S3 apoptosis and subG1 cells, but reduced viability, indicating the cytoprotective role of autophagy. HCC samples displayed higher FOXO3 levels, being associated with shorter survival and autophagic genes expression. Consistently, chemoresistant in vitro models showed significant FOXO3 upregulation. FOXO3 knockdown suppressed autophagy and caused resistant cell death, demonstrating that overactivation of such pro-survival autophagy during sorafenib resistance is FOXO3-dependent; a cytoprotective mechanism that the second-line drug regorafenib successfully abolished. Therefore, targeting FOXO3-mediated autophagy could significantly improve the clinical efficacy of sorafenib.
Highlights
Hepatocarcinoma (HCC), one of the deadliest tumors worldwide [1], is usually diagnosed at advanced stages [2]
In order to evaluate the effect of prolonged sorafenib treatment on autophagy modulation in our HCC in vitro models, we started with the assessment of the basal autophagic status of the two sorafenib-resistant lines and the parental cells HepG2
Forkhead box O3 (FOXO3) was associated with more malignant HCC phenotypes and with a pro-autophagic microenvironment, we addressed the hypothesis by which FOXO3 could mediate, at least in part, the activation of pro-survival autophagy in HCC cells during the acquisition of sorafenib resistance
Summary
Hepatocarcinoma (HCC), one of the deadliest tumors worldwide [1], is usually diagnosed at advanced stages [2]. Patients obtain a short survival benefit due to the apparition of sorafenib-resistant tumor hepatocytes within the first six months of treatment [2,3,4]. Autophagy is an evolutionarily conserved catabolic and recycling process by which damaged or redundant cellular components are engulfed into double-membrane vesicles—autophagosomes—in order to be degraded through the lysosomal pathway [8,9,10]. This process comprises autophagosome formation and maturation, autophagolysosome formation by fusion with the lysosome, and final cargo degradation [8,10]. This self-digestive mechanism plays an important physiological role in the liver as it is the major metabolic organ [9], and dysregulation of autophagy has been even related to several hepatic diseases including HCC [11]
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