Abstract
Statins, such as lovastatin, can induce a cell cycle arrest in the G1 phase. This robust antiproliferative activity remains intact in many cancer cells that are deficient in cell cycle checkpoints and leads to an increased expression of CDK inhibitor proteins p27Kip1 and p21Cip1. The molecular details of this statin-induced growth arrest remains unclear. Here we present evidence that lovastatin can induce the degradation of Skp2, a subunit of the SCFSkp2 ubiquitin ligase that targets p27Kip1 and p21Cip1 for proteasomal destruction. The statin-induced degradation of Skp2 is cell cycle phase independent and does not require its well characterised degradation pathway mediated by APC/CCdh1- or Skp2 autoubiquitination. An N-terminal domain preceding the F-box of Skp2 is both necessary and sufficient for its statin mediated degradation. The degradation of Skp2 results from statin induced depletion of geranylgeranyl isoprenoid intermediates of cholesterol biosynthesis. Inhibition of geranylgeranyl-transferase-I also promotes APC/CCdh1- independent degradation of Skp2, indicating that de-modification of a geranylgeranylated protein triggers this novel pathway of Skp2 degradation.
Highlights
Statins are a class of small fungal metabolites that inhibit the HMG-CoA reductase, an enzyme that catalyses the reduction of 3-hydroxy-3-methyl-glutarylCoA (HMG-CoA) to mevalonate [1]
Lovastatin caused a clear decline in the Skp2 protein level even in S-phase arrested cells, where Skp2 usually is relatively stable (Fig. 1A, + thymidine), demonstrating that the reduction of Skp2 occurs independently of the G1 arrest caused by lovastatin. p21 and p27 did not accumulate in S-phase arrested cells, probably because Skp2 levels remain generally elevated and these remaining levels of Skp2 may be sufficient to promote p21 and p27 degradation
As a main substrate of Skp2 is the CDK inhibitor p27 [19], we investigated if cells lacking p27 expression are less sensitive to lovastatin-induced cell cycle arrest
Summary
Statins are a class of small fungal metabolites that inhibit the HMG-CoA reductase, an enzyme that catalyses the reduction of 3-hydroxy-3-methyl-glutarylCoA (HMG-CoA) to mevalonate [1]. This is a ratelimiting step of the cholesterol biosynthesis pathway. For this reason statins have been used extensively for the treatment of hypercholesterolemia. It has been appreciated for some time that statins can induce growth arrest in several diverse cancer cell lines [2, 3]. Lipophilic statins were found to induce cell death in MCF-
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