Macro-autophagy (autophagy) is a highly conserved eukaryotic intracellular process of self-digestion caused by lysosomes on demand, which is upregulated as a survival strategy upon exposure to various stressors, such as metabolic insults, cytotoxic drugs, and alcohol abuse. Paradoxically, autophagy dysfunction also contributes to cancer and aging. It is well known that regulating autophagy by targeting specific regulatory molecules in its machinery can modulate multiple disease processes. Therefore, autophagy represents a significant pharmacological target for drug development and therapeutic interventions in various diseases, including cancers. According to the framework of autophagy, the suppression or induction of autophagy can exert therapeutic properties through the promotion of cell death or cell survival, which are the two main events targeted by cancer therapies. Remarkably, natural products have attracted attention in the anticancer drug discovery field, because they are biologically friendly and have potential therapeutic effects. In this review, we summarize the up-to-date knowledge regarding natural products that can modulate autophagy in various cancers. These findings will provide a new position to exploit more natural compounds as potential novel anticancer drugs and will lead to a better understanding of molecular pathways by targeting the various autophagy stages of upcoming cancer therapeutics.

Diabetes mellitus is a burdensome disease that affects various cellular functions through altered glucose metabolism. Several reports have linked diabetes to cancer development; however, the exact molecular mechanism of how diabetes-related traits contribute to cancer progression is not fully understood. The current study aimed to explore the molecular mechanism underlying the potential effect of hyperglycemia combined with hyperinsulinemia on the progression of breast cancer cells. To this end, gene dysregulation induced by the exposure of MCF7 breast cancer cells to hyperglycemia (HG), or a combination of hyperglycemia and hyperinsulinemia (HGI), was analyzed using a microarray gene expression assay. Hyperglycemia combined with hyperinsulinemia induced differential expression of 45 genes (greater than or equal to two-fold), which were not shared by other treatments. On the other hand, in silico analysis performed using a publicly available dataset (GEO: GSE150586) revealed differential upregulation of 15 genes in the breast tumor tissues of diabetic patients with breast cancer when compared with breast cancer patients with no diabetes. SLC26A11, ALDH1A3, MED20, PABPC4 and SCP2 were among the top upregulated genes in both microarray data and the in silico analysis. In conclusion, hyperglycemia combined with hyperinsulinemia caused a likely unique signature that contributes to acquiring more carcinogenic traits. Indeed, these findings might potentially add emphasis on how monitoring diabetes-related metabolic alteration as an adjunct to diabetes therapy is important in improving breast cancer outcomes. However, further detailed studies are required to decipher the role of the highlighted genes, in this study, in the pathogenesis of breast cancer in patients with a different glycemic index.

Parkinson’s disease (PD) is the second most common neurological disorder, pathologically characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) as well as the formation of Lewy bodies composed mainly of α-synuclein (α-syn) aggregates. It has been documented that abnormal aggregation of α-syn is one of the major causes of developing PD. In the current study, administration of ellagic acid (EA), a polyphenolic compound (10 mg/kg bodyweight), significantly decreased α-syn spreading and preserved dopaminergic neurons in a male C57BL/6 mouse model of PD. Moreover, EA altered the autophagic flux, suggesting the involvement of a restorative mechanism meditated by EA treatment. Our data support that EA could play a major role in the clearing of toxic α-syn from spreading, in addition to the canonical antioxidative role, and thus preventing dopaminergic neuronal death.

The loss of the E3 ligase Parkin, in a familial form of Parkinson’s disease, is thought to cause the failure of both the polyubiquitination of abnormal mitochondria and the consequent induction of mitophagy, resulting in abnormal mitochondrial accumulation. However, this has not been confirmed in patient autopsy cases or animal models. More recently, the function of Parkin as a redox molecule that directly scavenges hydrogen peroxide has attracted much attention. To determine the role of Parkin as a redox molecule in the mitochondria, we overexpressed various combinations of Parkin, along with its substrates FAF1, PINK1, and ubiquitin in cell culture systems. Here, we observed that the E3 Parkin monomer was surprisingly not recruited to abnormal mitochondria but self-aggregated with or without self-ubiquitination into the inner and outer membranes, becoming insoluble. Parkin overexpression alone generated aggregates without self-ubiquitination, but it activated autophagy. These results suggest that for damaged mitochondria, the polyubiquitination of Parkin substrates on the mitochondria is not indispensable for mitophagy.