Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy.

Beclin-1 is the firstly-identified mammalian protein of the autophagy machinery, which functions as a molecular scaffold for the assembly of PI3KC3 (class III phosphatidylinositol 3 kinase) complex, thus controlling autophagy induction and other cellular trafficking events. Notably, there is mounting evidence establishing the implications of Beclin-1 in diverse tumorigenesis processes, including tumor suppression and progression as well as resistance to cancer therapeutics and CSC (cancer stem-like cell) maintenance. More importantly, Beclin-1 has been confirmed as a potential target for the treatment of multiple cancers. In this review, we provide a comprehensive survey of the structure, functions, and regulations of Beclin-1, and we discuss recent advances in understanding the controversial roles of Beclin-1 in oncology. Moreover, we focus on summarizing the targeted Beclin-1-regulating strategies in cancer therapy, providing novel insights into a promising strategy for regulating Beclin-1 to improve cancer therapeutics in the future.

Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications.

UNC-51-like kinase 1 (ULK1), as a serine/threonine kinase, is an autophagic initiator in mammals and a homologous protein of autophagy related protein (Atg) 1 in yeast and of UNC-51 in Caenorhabditis elegans. ULK1 is well-known for autophagy activation, which is evolutionarily conserved in protein transport and indispensable to maintain cell homeostasis. As the direct target of energy and nutrition-sensing kinase, ULK1 may contribute to the distribution and utilization of cellular resources in response to metabolism and is closely associated with multiple pathophysiological processes. Moreover, ULK1 has been widely reported to play a crucial role in human diseases, including cancer, neurodegenerative diseases, cardiovascular disease, and infections, and subsequently targeted small-molecule inhibitors or activators are also demonstrated. Interestingly, the non-autophagy function of ULK1 has been emerging, indicating that non-autophagy-relevant ULK1 signaling network is also linked with diseases under some specific contexts. Therefore, in this review, we summarized the structure and functions of ULK1 as an autophagic initiator, with a focus on some new approaches, and further elucidated the key roles of ULK1 in autophagy and non-autophagy. Additionally, we also discussed the relationships between ULK1 and human diseases, as well as illustrated a rapid progress for better understanding of the discovery of more candidate small-molecule drugs targeting ULK1, which will provide a clue on novel ULK1-targeted therapeutics in the future.