Autophagy is a physiological degradative mechanism of the cells by which autophagic vesicles deliver unfolded proteins and damaged organelles to lysosomes for their elimination. In this way, autophagy induces the degradation and recycling of cellular components to support energy metabolism in stressing conditions and cellular homeostasis [1]. Accumulating evidence also demonstrates that autophagy declines with age and that impaired autophagy favors individuals to age-related diseases, whereas interventions that stimulate autophagy can promote longevity [2]. However, the excessive stimulation of autophagy can be considered a self-eating mechanism favoring cell death and the aberrant regulation of autophagy is widely studied to improve therapeutic treatments for various diseases including cancer [3]. In different stages of tumorigenesis, autophagy may have opposite and context-dependent roles acting as tumor suppressor or cancer promoter [4]. Many external stimuli may affect autophagy in cancer, such as hypoxia, acidification of tumor microenvironment, nutrient deprivation, drug therapies, or infections [5,6]. A global analysis of the mutational status of the genes encoding the entire core autophagy machinery reveals that it is generally not targeted by high-frequency somatic single-nucleotide mutations across cancers [7]. These large-scale analyses indicate that the core autophagy machinery largely escapes genomic mutations and cancer cells generally express a functionally intact autophagy pathway. An exception to this general scheme is represented by the tumor suppressor BECN1 (ATG6), which lost with high frequency one allele in various cancer types [8]. However, BECN1 is adjacent to the known tumor suppressor gene breast cancer 1 (BRCA1) on chromosome 17. Hereditary breast cancer commonly results from the presence of a pathogenic germline missense mutation in BRCA1 followed by somatic deletion of the remaining wild-type BRCA1 allele. These deletions are typically large, deleting BRCA1 along with hundreds of other genes, including BECN1. Further studies demonstrated that BRCA1 loss is the driver mutation in hereditary and sporadic breast cancer [9], casting doubt on BECN1′s role as a tumor suppressor. In cancers, the autophagic flux can be modulated by tumor suppressors or oncogenes. A crucial example is that of p53, the status of which can modify the role of autophagy in tumor progression [10,11]. Furthermore, several studies indicate that p53 triggers autophagy in cancer cells through various mechanisms, such as the stimulation of AMPK, the inhibition of mTOR, or the induction of the autophagy-related gene DRAM1, to react to genotoxic or environmental stimuli [12,13]. On the other side, mutant p53 proteins counteract the autophagic machinery by various molecular mechanisms, including the transcriptional repression of ATG12 [14]. Notably, mutant p53 protein stability is affected by lysosome-mediated degradation through autophagy, supporting the concept of a functional crosstalk between mutant p53 proteins and autophagy in cancer progression [15].

Curiously, even a glycolytic enzyme, i.e., glyceraldehyde-3-phosphate dehydrogenase (GAPDH), may regulate autophagy and cell death through mechanisms that we summarize in this review. In addition to the main glycolytic role of the tetrameric conformation of GAPDH, which catalyzes the reversible conversion of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate, GAPDH serves as a versatile enzyme that plays several regulatory roles determining the fate of the cells [16]. Indeed, GAPDH performs pleiotropic functions that mainly depend on its subcellular localization [17]. In addition to the cytosolic distribution of the glycolytic enzyme, GAPDH can also be detected close to the plasma membrane, mitochondria, nucleus, endoplasmic reticulum (ER), polysomes, Golgi and even secreted in the extracellular space carrying out several key functions including the regulation of mRNA stability [18], iron uptake and transport [19], DNA repair [20], nuclear tRNA export [21], cell death [22] and intracellular membrane trafficking [23]. The GAPDH multifunctional properties can be regulated by several mechanisms, such as the formation of macromolecular complexes by protein–protein interactions; post-translational modifications, e.g., acetylation, phosphorylation and nitrosylation; or protein oligomerization. The oligomeric state of GAPDH and its propensity to aggregate is mainly dependent on various signal molecules [24]. The redox sensitive cysteine residues of the enzyme, which includes Cys-152 in the active site, are also target of reactive oxygen species (ROS) or reactive nitrogen species (RNS) and, consequently, GAPDH aggregation is influenced by several other stimuli inducing cellular oxidative/nitrosative stresses [24,25]. Besides cancer, the functional versatility of this enzyme determines that GAPDH alteration is involved in several other diseases [26] especially neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD) [27].

Due to the non-glycolytic roles of GAPDH, this enzyme is considered a moonlight protein in the cells. These non-glycolytic roles include physio-pathological functions such as regulation of gene expression, DNA repair and replication, neurodegeneration, pathogenesis, virulence in bacteria, tubular bundling, protein–protein interactions, RNA export, as well as apoptosis and autophagy. For instance, it has been discovered that GAPDH acts as a key component of the co-activator complex of Oct-1 in the transcriptional induction of histone H2B gene during the S phase of the cell cycle. Intriguingly, GAPDH interacts directly with Oct-1 and it has an intrinsic activation domain that can relate with the general transcription machinery [28]. This proof-of-concept opened the way to the investigation of target genes which can be transcriptionally regulated by nuclear GAPDH.

Concerning autophagy, it has been demonstrated that GAPDH may also act as a glucose sensor in the cells stimulating autophagic degradation. Indeed, during glucose starvation, the AMPK-dependent GAPDH phosphorylation is essential for SIRT1 activation and stimulation of autophagy. In these conditions, cytoplasmic GAPDH is phosphorylated by activated AMPK prompting GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH directly interacts with SIRT1, displacing SIRT1’s repressor and increasing SIRT1 deacetylase activity [29]. In general, the multiple activities of GAPDH are related to its translocation to the nucleus or to different subcellular compartments in addition to the cytosolic localization, where its main role in glycolysis is well characterized.

The subcellular and glycolytic-independent redistribution of the enzyme can mainly occur in the nucleus, mitochondria, and intra- and extra-cellular vesicles. The regulation of GAPDH compartmentalization is mainly due to its oligomerization, post-transcriptional modifications and protein–protein interactions, thus defining also the non-glycolytic functions of GAPDH. These findings are schematically represented in Figure 1.