Cyclin D1 Degradation Is Sufficient to Induce G1 Cell Cycle Arrest despite Constitutive Expression of Cyclin E2 in Ovarian Cancer Cells

Abstract

D-and E-type cyclins mediate G 1 -S phase cell cycle progression through activation of specific cyclin-dependent kinases (cdk) that phosphorylate the retinoblastoma protein (pRb), thereby alleviating repression of E2F-DP transactivation of S-phase genes. Cyclin D1 is often overexpressed in a variety of cancers and is associated with tumorigenesis and metastasis. Loss of cyclin D can cause G 1 arrest in some cells, but in other cellular contexts, the downstream cyclin E protein can substitute for cyclin D and facilitate G 1 -S progression. The objective of this study was to determine if a flexible heteroarotinoid anticancer compound, SHetA2, regulates cell cycle proteins and cell cycle progression in ovarian cancer cells. SHetA2 induced cyclin D1 phosphorylation, ubiquitination, and proteasomal degradation, causing G 1 arrest in ovarian cancer cells despite continued cyclin E2 expression and independently of p53 and glycogen synthase kinase-3B. Cyclin D1 loss inhibited pRb S780 phosphorylation by cyclin D1-cdk4/6 and released p21 from cyclin D1-cdk4/6-p21 protein complexes to form cyclin E2-cdk2-p21 complexes, which repressed phosphorylation of pRb S612 by cyclin E2-cdk2 and ultimately E2F-DP transcriptional activity. G 1 arrest was prevented by overexpression or preventing degradation of cyclin D1 but not by restoration of pRb S612 phosphorylation through p21 knockdown. In conclusion, we show that loss of cyclin D1 in ovarian cancer cells treated with SHetA2 is sufficient to induce G 1 cell cycle arrest and this strategy is not impeded by the presence of cyclin E2. Therefore, cyclin D1 is a sufficient therapeutic target in ovarian cancer cells. [Cancer Res 2009;69(16):6565-72]

Expression Profiling and Biochemical Analysis Suggest Stress Response as a Potential Mechanism Inhibiting Proliferation of Polyamine-depleted Cells

“…The G 1 arrest in polyamine-depleted cells was associated with increased transcription of p21 and Gadd45a, decreased transcription of Cdk2, E2f1, Pcna, cyclins A and E, and most profoundly with decreased levels of the cyclin D1 protein, a regulator of the Cdks required for G 1 /S transition, whose decline was demonstrated to suffice for arresting cellular proliferation (40,65).…”

Cytotoxic effect ofErythroxylum daphnitesextract is associated with G1cell cycle arrest and apoptosis in oral squamous cell carcinoma

“…31 Many of these mutations are found in genes that regulate cell cycle G 1 phase progression. 32,33 Once the cell progresses from G 1 to S phase; it is committed to DNA replication Figure 2. The hexane extract of Erythroxylum daphnites extract (EDH) decreases the proliferation of SCC-9 tongue carcinoma cells.…”

“…and cell division. 33 Apoptosis is a fundamental mechanism in various stages of development and actively participates in immune system regulation and homeostasis in multicellular organisms. Failure to control apoptosis might be an underlying cause of several diseases, such as neurodegenerative diseases, autoimmune diseases, and cancer.…”

Acylglycerol kinase promotes the proliferation and cell cycle progression of oral squamous cell carcinoma

“…Cyclin D1 is a vital protein that positively regulates cell cycle progression through the G 1 to S phase transition (18,19). Aberrant cyclin D1 expression has been shown to contribute to the loss of normal cell cycle control (20), and cyclin D1 degradation is sufficient to induce G 0 /G 1 cell cycle arrest in cancer cells (21)(22)(23). The transition to S phase is induced by the activation of the cyclin D/CDK complex, which phosphorylates Rb, a well-characterized regulator of cell proliferation (9,24,25).…”