Out of the cycle: Impact of cell cycle aberrations on cancer metabolism and metastasis

Abstract

The use of cell cycle inhibitors has necessitated a better understanding of the cell cycle in tumor biology to optimize the therapeutic approach. Cell cycle aberrations are common in cancers, and it is increasingly acknowledged that these aberrations exert oncogenic effects beyond the cell cycle. Multiple facets such as cancer metabolism, immunity and metastasis are also affected, all of which are beyond the effect of cell proliferation alone. This review comprehensively summarized the important recent findings and advances in these interrelated processes. In cancer metabolism, cell cycle regulators can modulate various pathways in aerobic glycolysis, glucose uptake and gluconeogenesis, mainly through transcriptional regulation and kinase activities. Amino acid metabolism is also regulated through cell cycle progression. On cancer metastasis, metabolic plasticity, immune evasion, tumor microenvironment adaptation and metastatic site colonization are intricately related to the cell cycle, with distinct regulatory mechanisms at each step of invasion and dissemination. Throughout the synthesis of current understanding, knowledge gaps and limitations in the literature are also highlighted, as are new therapeutic approaches such as combinational therapy and challenges in tackling emerging targeted therapy resistance. A greater understanding of how the cell cycle modulates diverse aspects of cancer biology can hopefully shed light on identifying new molecular targets by harnessing the vast potential of the cell cycle.

Restoring gluconeogenesis by TEF inhibited proliferation and promoted apoptosis and immune surveillance in kidney renal clear cell carcinoma

“…Our study also found that miR-4477b inhibited gluconeogenesis by restricting TEF and FBP1, while TEF promoted gluconeogenesis by transcriptionally regulating PCK1 and PCK2. TEF was previously reported to retard bladder cancer cell growth by inhibiting G1/S transition and regulating AKT/FOXOs signaling, which are both closely related to glycolysis/gluconeogenesis homeostasis [ 43 – 45 ]. Interestingly, our research did not identify any other miRNAs previously reported to regulate gluconeogenesis under various conditions (miR-158-5p, miR-351, miR-451, etc.)…”

MLK4 promotes glucose metabolism in lung adenocarcinoma through CREB-mediated activation of phosphoenolpyruvate carboxykinase and is regulated by KLF5

“…Our study demonstrated that the KLF5-MLK4-PCK1 axis exerts an oncogenic function in lung carcinogenesis with altered glucose metabolism. These findings are interesting in that we unraveled the unusual link between a kinase chiefly involved in the cell cycle progression and a metabolic enzyme [ 24 ]. Moreover, we showed that MLK4 and PCK1 are oncogenic factors in lung cancer with potential clinical and prognostic significance.…”

“…We demonstrated that PCK1 expression could be high in a significant subset of patients using immunohistochemistry on tissue microarray, that it was significantly correlated with a worse prognosis, and that it was regulated by MLK4 and CREB in low glucose media conditions. Meanwhile, CREB was well-known to regulate the transcription of PCK1, at least in gluconeogenic tissues [ 24 , 28 ]. By siRNA-mediated CREB inhibition and selective pharmacologic inhibitor of CREB, we demonstrated that this regulation of PCK1 by CREB was also present in lung adenocarcinoma.…”

Schisantherin A inhibits cell proliferation by regulating glucose metabolism pathway in hepatocellular carcinoma

“…An increase in the degree of glycolysis in tumors occurs to meet the energy demands of rapidly proliferating tumor cells, and glycolysis can also produce intermediate metabolites supporting the biosynthesis of nucleotides, amino acids, and lipids, thus allowing the rapid proliferation of tumor cells ( Feng et al, 2020 ). Glucose metabolism is coupled to cell cycle progression, and glucose metabolism ensures adequate ATP and synthetic metabolites at different stages of the cell cycle ( Cheung et al, 2022 ). 6-Phosphofructo-2-kinase (PFKFB3) can promote cell cycle progression through CDK1-mediated phosphorylation of P27 ( Yalcin et al, 2014 ).…”