The Intricate Interplay between Cell Cycle Regulators and Autophagy in Cancer

Simple Summary Autophagy is an intracellular catabolic program regulated by multiple external and internal cues. A large amount of evidence unraveled that cell-cycle regulators are crucial in its control. This review highlights the interplay between cell-cycle regulators, including cyclin-dependent kinase inhibitors, cyclin-dependent kinases, and E2F factors, in the control of autophagy all along the cell cycle. Beyond the intimate link between cell cycle and autophagy, this review opens therapeutic perspectives in modulating together these two aspects to block cancer progression. In the past decade, cell cycle regulators have extended their canonical role in cell cycle progression to the regulation of various cellular processes, including cellular metabolism. The regulation of metabolism is intimately connected with the function of autophagy, a catabolic process that promotes the efficient recycling of endogenous components from both extrinsic stress, e.g., nutrient deprivation, and intrinsic sub-lethal damage. Mediating cellular homeostasis and cytoprotection, autophagy is found to be dysregulated in numerous pathophysiological contexts, such as cancer. As an adaptative advantage, the upregulation of autophagy allows tumor cells to integrate stress signals, escaping multiple cell death mechanisms. Nevertheless, the precise role of autophagy during tumor development and progression remains highly context-dependent. Recently, multiple articles has suggested the importance of various cell cycle regulators in the modulation of autophagic processes. Here, we review the current clues indicating that cell-cycle regulators, including cyclin-dependent kinase inhibitors (CKIs), cyclin-dependent kinases (CDKs), and E2F transcription factors, are intrinsically linked to the regulation of autophagy. As an increasing number of studies highlight the importance of autophagy in cancer progression, we finally evoke new perspectives in therapeutic avenues that may include both cell cycle inhibitors and autophagy modulators to synergize antitumor efficacy.