Roscovitine, a selective CDK inhibitor, reduces the basal and estrogen‐induced phosphorylation of ER‐α in human ER‐positive breast cancer cells

Abstract

Roscovitine (ROSC), a selective cyclin-dependent kinase (CDK) inhibitor, arrests human estrogen receptor-α (ER-α) positive MCF-7 breast cancer cells in the G(2) phase of the cell cycle and concomitantly induces apoptosis via a p53-dependent pathway. The effect of ROSC is markedly diminished in MCF-7 cells maintained in the presence of estrogen-mimicking compounds. Therefore, we decided to examine whether ROSC has any effect on the functional status of the ER-α transcription factor. Exposure of MCF-7 cells to ROSC abolished the activating phosphorylation of CDK2 and CDK7 in a concentration and time-dependent manner. This inhibition of site-specific modification of CDK7 at Ser164/170 prevented phosphorylation of RNA polymerase II and reduced basal phosphorylation of ER-α at Ser118 in non-stimulated MCF-7 cells (resulting in its down-regulation). In MCF-7 cells, estrogen induced strong phosphorylation of ER-α at Ser118 but not at Ser104/Ser106. ROSC prevented this estrogen-promoted activating modification of ER-α. Furthermore, we sought to determine whether the activity of ROSC could be enhanced by combining it with an anti-estrogen. Tamoxifen (TAM), a selective estrogen receptor modulator (SERM), affected breast cancer cell lines irrespective of their ER status. In combination with ROSC, however, it had a different impact, enhancing G(1) or G(2) arrest. Our results indicate that ROSC prevents the activating phosphorylation of ER-α and that its mode of action is strongly dependent on the cellular context. Furthermore, our data show that ROSC can be combined with anti-estrogen therapy. The inhibitory effect of TAM on ER-negative cancer cells indicates that SERMs crosstalk with other steroid hormone receptors.

Roscovitine confers tumor suppressive effect on therapy-resistant breast tumor cells

“…Our findings suggest that the reduction in ERα levels in the resistant cells is due to both transcriptional and post-translational effects by roscovitine. Our data corroborate data from a recent study that demonstrated a reduction in ERα levels in MCF7 cells after roscovitine treatment, which possibly occurred through the inhibition of CDK7 [53]. As many endocrine therapy-resistant cells retain expression and functionality of ERα, the ability of roscovitine to down regulate the ERα axis, may also have contributed to its ability to curb the progression of the resistant cells.…”

Cyclin E2 Overexpression Is Associated with Endocrine Resistance but not Insensitivity to CDK2 Inhibition in Human Breast Cancer Cells

“…Decreases in ER expression or transcriptional activity provide a potential mechanism for this effect. Phosphorylation by CDK2 activates ERa, and this effect is enhanced by CDK7 (47), so that inhibition of these CDKs inhibits ERa transcriptional activity (44,48). In addition, the CDK inhibitor roscovitine decreases ERa expression (44,48).…”

CR8, a Selective and Potent CDK Inhibitor, Provides Neuroprotection in Experimental Traumatic Brain Injury

“…More than 140 CDK inhibitors have been described, of which 10 are currently undergoing phase 1 or phase 2 clinical trials as anti-cancer agents [19]. Roscovitine (also known as CYC202 or seliciclib) is a 2,6,9-tri-substituted purine that is in late phase 2 trials for non-small cell lung cancer and nasopharyngeal cancer [14, 15, 19]. Roscovitine has demonstrated selectivity for certain kinases, including CDKs-1, -2, -5, -7, and –9; other potentially attractive features are its oral bioavailabilty and more modest toxicity than other such inhibitors [19].…”

“…We have previously investigated the neuroprotective potential of a relatively selective CDK inhibitor roscovitine, which is currently being evaluated clinically for the treatment of certain cancers [14–16]. Roscovitine attenuates CCA, progressive neurodegeneration, and neurological dysfunction in several models of TBI [17, 18].…”