Abstract
Autophagy is an essential process of the eukaryotic cell allowing degradation and recycling of dysfunctional cellular components in response to either physiological or pathological changes. Inhibition of autophagy in combination with chemotherapeutic treatment has emerged as a novel approach in cancer treatment leading to cell cycle arrest, differentiation, and apoptosis. Suberoyl hydroxamic acid (SAHA) is a broad-spectrum histone deacetylase inhibitor (HDACi) suppressing family members in multiple HDAC classes. Increasing evidence indicates that SAHA and other HDACi can, in addition to mitochondria-mediated apoptosis, also promote caspase-independent autophagy. SAHA-induced mTOR inactivation as a major regulator of autophagy activating the remaining autophagic core machinery is by far the most reported pathway in several tumor models. However, the question of which upstream mechanisms regulate SAHA-induced mTOR inactivation that consequently initiate autophagy has been mainly left unexplored. To elucidate this issue, we recently initiated a study clarifying different modes of SAHA-induced cell death in two human uterine sarcoma cell lines which led to the conclusion that the tumor suppressor protein p53 could act as a molecular switch between SAHA-triggered autophagic or apoptotic cell death. In this review, we present current research evidence about HDACi-mediated apoptotic and autophagic pathways, in particular with regard to p53 and its therapeutic implications.
Highlights
The Significance of Autophagy in Tumor CellsResistance to cell death induction has been identified as a hallmark of cancer [1,2]
Considerable research efforts are in progress to investigate the molecular pathways regulating histone deacetylase inhibitor (HDACi)-mediated cell death in tumor cells
Autophagy induced by p53 may facilitate p53’s cell cycle arrest activities, such that autophagy mediates the selective degradation of damaged molecules and organelles to provide an energy source for the damage repair process and promote “cell healing”
Summary
Resistance to cell death induction has been identified as a hallmark of cancer [1,2]. If autophagy is mediated in tumor cells where apoptosis resistance is encountered frequently, it seems to provide a cytoprotective function to limit tumor necrosis and inflammation and thereby presumes a tumor suppressive function [8] In this context, autophagy may be regarded as a pro-survival mechanism and has been shown to simultaneously inhibit the onset of apoptotic and necrotic cell death [3,9,10,11,12]. In cases where autophagy may have an auxiliary role in the death process, cell death is presumably induced by accelerating the “self-eating” program through yet unknown mechanisms [13] If this aspect of autophagy is suppressed by autophagosomal dysfunction, it will lead to prolonged tumor survival, i.e., a tumor-promoting function. Presumably additional factors such as stress, molecular subtype, and microenvironmental conditions could influence autophagy (reviewed by [20])
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