Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK–LKB1 Signaling Axis

Casimiro, Mathew C.; Sante, Gabriele Di; Rocco, Agnese Di; Loro, Emanuele; Pupo, Claudia; Pestell, Timothy G.; Bisetto, Sara; Velasco-Velázquez, Marco A.; Jiao, Xuanmao; Li, Zhiping; Kusminski, Christine M.; Seifert, Erin L.; Wang, Chenguang; Ly, Daniel; Zheng, Bin; Shen, Che Hung; Scherer, Philipp E.; Pestell, Richard G.

doi:10.1158/0008-5472.can-16-0425

Cited by 52 publications

(45 citation statements)

References 53 publications

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“…In fasting mice, cyclin D1 induced hepatocyte steatosis and evidence of decreased lipolysis and autophagy, suggesting that these mechanisms also occur in vivo. In contrast to a recent study, we found that cyclin D1 did not appear to inhibit AMPK activation, indicating that a different mechanism of autophagy regulation occurs in hepatocytes. Dissecting the mechanistic links between cyclin D1 and lipophagy may provide insight into the regulation of LD accumulation in liver regeneration and fatty liver.…”

Section: Discussioncontrasting

confidence: 99%

“…It is now recognized that LD catabolism in hepatocytes is also regulated by degradation through autophagic mechanisms (lipophagy), which recently has been mechanistically linked to ATGL . We found that cyclin D1 inhibited autophagy in hepatic cells, as has been shown in other cell types . Our studies also provide novel evidence that cyclin D1 inhibits lipophagy and LAL‐mediated lipolysis and that this is likely to be a key mechanism by which cyclin D1 promotes LD accumulation.…”

Section: Discussionsupporting

confidence: 79%

“…B). A recent study in other cell types found that cyclin D1 inhibited the activation of AMPK as measured by the western blot of Thr‐172‐phosphorylated AMPK, providing a potential mechanism of autophagy inhibition . In contrast, we found that cyclin D1 knockdown moderately decreased the abundance of the activated (Thr‐172) AMPK, suggesting that its regulation (and link to autophagy) is distinct in hepatocytes (Supporting Fig.…”

Section: Resultsmentioning

confidence: 43%

“…For example, a recent paper demonstrated that ATGL triggers lipophagy in hepatocytes and that autophagy regulators are required for ATGL‐mediated lipolysis, indicating that the two processes are interconnected . Prior studies in other cell types have found that cyclin D1 can repress autophagy . We therefore examined whether cyclin D1 regulates autophagy and lipophagy in AML12 cells.…”

Section: Resultsmentioning

confidence: 96%

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

Ploeger

Kamarajugadda

et al. 2019

Hepatol Commun

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During normal proliferation, hepatocytes accumulate triglycerides (TGs) in lipid droplets (LDs), but the underlying mechanisms and functional significance of this steatosis are unknown. In the current study, we examined the coordinated regulation of cell cycle progression and LD accumulation. As previously shown, hepatocytes develop increased LD content after mitogen stimulation. Cyclin D1, in addition to regulating proliferation, was both necessary and sufficient to promote LD accumulation in response to mitogens. Interestingly, cyclin D1 promotes LD accumulation by inhibiting the breakdown of TGs by lipolysis through a mechanism involving decreased lipophagy, the autophagic degradation of LDs. To examine whether inhibition of lipolysis is important for cell cycle progression, we overexpressed adipose TG lipase (ATGL), a key enzyme involved in TG breakdown. As expected, ATGL reduced LD content but also markedly inhibited hepatocyte proliferation, suggesting that lipolysis regulates a previously uncharacterized cell cycle checkpoint. Consistent with this, in mitogen‐stimulated cells with small interfering RNA‐mediated depletion of cyclin D1 (which inhibits proliferation and stimulates lipolysis), concurrent ATGL knockdown restored progression into S phase. Following partial hepatectomy, a model of robust hepatocyte proliferation in vivo, ATGL overexpression led to decreased LD content, cell cycle inhibition, and marked liver injury, further indicating that down‐regulation of lipolysis is important for normal hepatocyte proliferation. Conclusion: We suggest a new relationship between steatosis and proliferation in hepatocytes: cyclin D1 inhibits lipolysis, resulting in LD accumulation, and suppression of lipolysis is necessary for cell cycle progression.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 79%

Section: Resultsmentioning

confidence: 43%

Section: Resultsmentioning

confidence: 96%

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

Ploeger

Kamarajugadda

et al. 2019

Hepatol Commun

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“…18,19 Some have argued that Cyclin D1 can inhibit AMPK activation which may link the CDK4/6 inhibitors to autophagy. 20 Knock down of Cyclin D1 enhanced the phosphorylation of AMPKα T172 whereas over-expression of the cyclin prevented metabolic stresses from increasing T172 levels; this was linked to Cyclin D1/CDK4/6 phosphorylating and inactivating LKB-1. Unfortunately, these authors used 5-fold greater concentrations of palbociclib to our own which is above the safe plasma C max concentration, and our ability of palbociclib to enhance AMPKα T172 phosphorylation occurs in cells with very low/no LKB-1 expression such as HT1080 (sarcoma), A549 and H460 (NSCLC) and HCT116 (colon).…”

Section: Discussionmentioning

confidence: 98%

Palbociclib augments Neratinib killing of tumor cells that is further enhanced by HDAC inhibition

Booth

Roberts

Rais

et al. 2018

Cancer Biology & Therapy

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Cancers expressing mutant RAS are associated with a weaker response to chemotherapy and a shorter overall patient survival. We have demonstrated that the irreversible inhibitor of ERBB1/2/4, neratinib, inhibits ERBB1/2/4 and causes their internalization and autolysosomal degradation. Fellow-traveler membrane proteins with RTKs, including mutant K-/N-RAS, were also degraded. We discovered that the CDK4/6 inhibitor palbociclib increased autophagosome and then autolysosome levels in a time dependent fashion, did not reduce mTOR activity, and interacted with temsirolimus to kill. Neratinib and palbociclib interacted in a greater than additive manner to increase autophagosome and then autolysosome levels in a time dependent fashion, and to cause tumor cell killing. Killing required the expression of ATM and AMPKα, Beclin1 and ATG5, BAX and BAK and of AIF, but not of caspase 9. In some cells over-expression of BCL-XL was protective whereas in others it was ineffective. The lethality of [neratinib + palbociclib] was modestly enhanced by the PDE5 inhibitor sildenafil and strongly enhanced by the HDAC inhibitor sodium valproate. This was associated with K-RAS degradation and a greater than additive increase in autophagosome and autolysosome levels. Killing by the three-drug combination required ATM and AMPKα, and, to a greater extent, Beclin1 and ATG5. In vivo, [valproate + palbociclib] and [neratinib + valproate + palbociclib] interacted to suppress the growth of a carboplatin/paclitaxel resistant PDX ovarian tumors that express a mutant N-RAS. Our data support performing a future three-drug trial with these agents.

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CDK4/6 Inhibitors Impede Chemoresistance and Inhibit Tumor Growth of Small Cell Lung Cancer

Wen,

Sun,

Zeng

et al. 2024

Advanced Science

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Small cell lung cancer (SCLC) is characterized by rapid development of chemoresistance and poor outcomes. Cyclin‐dependent kinase 4/6 inhibitors (CDK4/6is) are widely used in breast cancer and other cancer types. However, the molecular mechanisms of CDK4/6 in SCLC chemoresistance remain poorly understood. Here, Rb1flox/flox, Trp53flox/flox, Ptenflox/flox (RTP) and Rb1flox/flox, Trp53flox/flox, MycLSL/LSL (RPM) spontaneous SCLC mouse models, SCLC cell line‐derived xenograft (CDX) models, and SCLC patient‐derived xenograft (PDX) models are established to reveal the potential effects of CDK4/6is on SCLC chemoresistance. In this study, it is found that CDK4/6is palbociclib (PD) or ribociclib (LEE) combined with chemotherapeutic drugs significantly inhibit SCLC tumor growth. Mechanistically, CDK4/6is do not function through the classic Retionblastoma1 (RB) dependent axis in SCLC. CDK4/6is induce impair autophagy through the AMBRA1‐lysosome signaling pathway. The upregulated AMBRA1 protein expression leads to CDK6 degradation via autophagy, and the following TFEB and TFE3 nuclear translocation inhibition leading to the lysosome‐related genes levels downregulation. Moreover, it is found that the expression of CDK6 is higher in SCLC tumors than in normal tissue and it is associated with the survival and prognosis of SCLC patients. Finally, these findings demonstrate that combining CDK4/6is with chemotherapy treatment may serve as a potential therapeutic option for SCLC patients.

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Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK–LKB1 Signaling Axis

Cited by 52 publications

References 53 publications

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

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

Palbociclib augments Neratinib killing of tumor cells that is further enhanced by HDAC inhibition

CDK4/6 Inhibitors Impede Chemoresistance and Inhibit Tumor Growth of Small Cell Lung Cancer

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