A Late G1 Lipid Checkpoint That Is Dysregulated in Clear Cell Renal Carcinoma Cells

Abstract

Lipids are important nutrients that proliferating cells require to maintain energy homeostasis as well as to build plasma membranes for newly synthesized cells. Previously, we identified nutrient-sensing checkpoints that exist in the latter part of the G phase of the cell cycle that are dependent upon essential amino acids, Gln, and finally, a checkpoint mediated by mammalian target of rapamycin (mTOR), which integrates signals from both nutrients and growth factors. In this study, we have identified and temporally mapped a lipid-mediated G checkpoint. This checkpoint is located after the Gln checkpoint and before the mTOR-mediated cell cycle checkpoint. Intriguingly, clear cell renal cell carcinoma cells (ccRCC) have a dysregulated lipid-mediated checkpoint due in part to defective phosphatase and tensin homologue (PTEN). When deprived of lipids, instead of arresting in G, these cells continue to cycle and utilize lipid droplets as a source of lipids. Lipid droplets have been known to maintain endoplasmic reticulum homeostasis and prevent cytotoxic endoplasmic reticulum stress in ccRCC. Dysregulation of the lipid-mediated checkpoint forces these cells to utilize lipid droplets, which could potentially lead to therapeutic opportunities that exploit this property of ccRCC.

Cell Cycle Progression Regulates Biogenesis and Cellular Localization of Lipid Droplets

“…These data suggest that cell cycle progression and lipid homeostasis are coordinated by a shared mechanism acting at the G 1 /S transition, thus implying that lipid droplet maintenance, biogenesis, or consumption is involved in cell cycle progression through S phase. In fact, a lipid-dependent metabolic checkpoint was recently described in late G 1 phase (51). Moreover, the fast lipid droplet dispersion within S phase identified in our study through BrdU staining is correlated with different stages of DNA synthesis, suggesting that molecules involved in the G 1 /S transition or S-phase progression could be acting in this process.…”

Evidence for a Novel Regulatory Interaction Involving Cyclin D1, Lipid Droplets, Lipolysis, and Cell Cycle Progression in Hepatocytes

“…Interestingly, prior studies have suggested that proteins that promote lipolysis, such as ATGL and CGI‐58, may act as tumor suppressor proteins through unknown mechanisms . Recent studies have also begun to elucidate distinct lipid‐mediated cell cycle checkpoints in other systems, and thus new interactions between lipid metabolism and cell proliferation are likely to be clarified by ongoing work.…”

Albumin promotes the progression of fibroblasts through late G1 into S-phase in the absence of growth factors

“…Commitment could be achieved with as little a 1 h treatment with plateletderived growth factor, whereas progression was more complicated involving IGF1 and other undetermined factor(s) in serum [11,12]. We recently identified a late G 1 cell cycle checkpoint that monitored the presence of fatty acids (FAs) [5]. We therefore wanted to determine whether lipids in serum contribute to late G 1 cell cycle progression into S-phase.…”

“…There are several metabolic checkpoints in late G 1 that check for both nutrient sufficiency and genomic integrity [1,2]. The metabolic checkpoints monitor the presence of essential amino acids, glutamine, and lipids [5,6]. There is also a checkpoint mediated by mammalian target of rapamycin complex 1 (mTORC1) [6,7].…”

“…We previously identified a late G 1 cell cycle checkpoint for lipids upstream from a mTORC1-mediated checkpoint and downstream from the mid-G 1 Restriction point [5]. We wanted to investigate a role for lipids in progression through late G 1 into S-phase.…”