Cell cycle on the crossroad of tumorigenesis and cancer therapy

The cell cycle machinery regulates cancer metabolism primarily at the post-translational level, either through phosphorylation of metabolic enzymes or upstream regulators by CDKs or through ubiquitination of these proteins by APC/C or SCF E3 ligases. CDK inhibitors restore cancer immune surveillance, in part by triggering tumor antigen presentation or stimulating the infiltration of immune cells into the tumor, thus providing synergetic effects with immune checkpoint blockade (ICB). Proteolysis targeting chimeras (PROTACs) provide a new cancer therapeutic approach to target cell cycle machinery components with oncogenic roles for proteasomal degradation, which has advantages over traditional small molecular inhibitors (SIMs) in many aspects including distinguishing the protein target from close family members, overcoming potential drug resistance, and repressing the kinase-independent function of protein targets. Aberrancy in cell cycle progression is one of the fundamental mechanisms underlying tumorigenesis, making regulators of the cell cycle machinery rational anticancer therapeutic targets. A growing body of evidence indicates that the cell cycle regulatory pathway integrates into other hallmarks of cancer, including metabolism remodeling and immune escape. Thus, therapies against cell cycle machinery components can not only repress the division of cancer cells, but also reverse cancer metabolism and restore cancer immune surveillance. Besides the ongoing effects on the development of small molecule inhibitors (SMIs) of the cell cycle machinery, proteolysis targeting chimeras (PROTACs) have recently been used to target these oncogenic proteins related to cell cycle progression. Here, we discuss the rationale of cell cycle targeting therapies, particularly PROTACs, to more efficiently retard tumorigenesis. Aberrancy in cell cycle progression is one of the fundamental mechanisms underlying tumorigenesis, making regulators of the cell cycle machinery rational anticancer therapeutic targets. A growing body of evidence indicates that the cell cycle regulatory pathway integrates into other hallmarks of cancer, including metabolism remodeling and immune escape. Thus, therapies against cell cycle machinery components can not only repress the division of cancer cells, but also reverse cancer metabolism and restore cancer immune surveillance. Besides the ongoing effects on the development of small molecule inhibitors (SMIs) of the cell cycle machinery, proteolysis targeting chimeras (PROTACs) have recently been used to target these oncogenic proteins related to cell cycle progression. Here, we discuss the rationale of cell cycle targeting therapies, particularly PROTACs, to more efficiently retard tumorigenesis. a multisubunit E3 ubiquitin ligase complex that targets cell cycle regulatory proteins for degradation by the 26S proteasome during the exit from mitosis and in the G1 phase of the cell cycle. In APC/C, the Cdh1 and Cdc20 subunits determine the specificity of the ubiquitination substrate. a control mechanism that halts cell cycle progression to ensure the accurate replication of genomic DNA and faithful separation of the sister chromatids into daughter cells. a technique for visualizing cell cycle progression in living cells, in which G1-phase cells express RFP-Cdt1 with red fluorescence and S/G2/M-phases cell green GFP-geminin. a metabolic process occurring in mitochondria, in which glutamine is lysed to glutamate to feed the TCA cycle. also known as immune checkpoint inhibition (ICI); refers to antibodies binding with immune checkpoint proteins to prevent their interaction with the corresponding receptor/ligand. Representative ICBs include PD-1 monoclonal antibody (mAb), PD-L1 mAb, and CTLA-4 mAb. a process occurring in mitochondria, which transfers electrons from the reductive NADH or FADH2 to oxygen by a series of electron carriers to produce ATP. also known as the hexose monophosphate shunt; a metabolic pathway parallel to glycolysis that uses glucose 6-phosphate to generate reductive DNAPDH and ribose 5-phosphate as a precursor for nucleotide synthesis. also known as serine/threonine-protein kinase 13 (STPK13). a heterobifunctional small molecule comprising a ligand to recruit E3 ubiquitin ligase, a moiety to recognize POIs, and a linker region, which bridges the transfer of polyubiquitin chains from the E3 ubiquitin ligase onto the POI for ubiquitination and the subsequent proteasomal degradation of the POI. a multiple-protein E3 ubiquitin ligase complex comprising the scaffold Cullin 1, the E2-recruiting subunit Rbx1, the adaptor protein Skp1 that binds to the F-box motif, and the substrate-binding F-box protein. also known as the mitotic checkpoint; a cell cycle checkpoint during mitosis or meiosis that ensures the proper transition from metaphase to anaphase and accurate separation of the duplicated chromatids. also known as the Krebs cycle or the citric acid cycle; a metabolic process that occurs in mitochondria, through which acetyl-CoA is lysed to CO2 in an enzymatic chain reaction to produce ATP and NADH. a metabolic phenotype of cancer cells, which is characterized by the favoring of glycolysis rather than the TCA cycle for carbohydrate metabolism.