Cytoplasmic cyclin D1 regulates glioblastoma dissemination

Abstract

Glioblastoma (GBM) is a highly invasive brain neoplasia with an elevated recurrence rate after surgical resection. The cyclin D1 (Ccnd1)/Cdk4-retinoblastoma 1 (RB1) axis is frequently altered in GBM, leading to overproliferation by RB1 deletion or by Ccnd1-Cdk4 overactivation. High levels of Ccnd1-Cdk4 also promote GBM cell invasion by mechanisms that are not so well understood. The purpose of this work is to elucidate the in vivo role of cytoplasmic Ccnd1-Cdk4 activity in the dissemination of GBM. We show that Ccnd1 activates the invasion of primary human GBM cells through cytoplasmic RB1-independent mechanisms. By using GBM mouse models, we observed that evaded GBM cells showed cytoplasmic Ccnd1 colocalizing with regulators of cell invasion such as RalA and paxillin. Our genetic data strongly suggest that, in GBM cells, the Ccnd1-Cdk4 complex is acting upstream of those regulators. Accordingly, expression of Ccnd1 induces focal adhesion kinase, RalA and Rac1 activities. Finally, in vivo experiments demonstrated increased GBM dissemination after expression of membrane-targeted Ccnd1. We conclude that Ccnd1-Cdk4 activity promotes GBM dissemination through cytoplasmic and RB1-independent mechanisms. Therefore, inhibition of Ccnd1-Cdk4 activity may be useful to hinder the dissemination of recurrent GBM.

Antitumor Effects of 5-Aminolevulinic Acid on Human Malignant Glioblastoma Cells

“…Targeting the cell-cycle machinery, particularly mitotic proteins, represents a promising therapeutic strategy to combat GBM [ 42 ]. The expression of cyclin D1 has been shown to be directly correlated with the progression and dissemination of GBM [ 43 , 44 ]. Inhibition of cyclin D1 has resulted in enhanced sensitivity of glioma cells to temozolomide, pointing to its key role in the chemoresistance of GBM cells [ 45 ].…”

The double dealing of cyclin D1

“…However, it was mostly cytoplasmic in the more aggressive, blastoid form of the disease [63]. In glioblastoma, cyclin D1 is mostly cytoplasmic in evading cells but retained within the nucleus in the tumor mass [64]. These observations confirm that cyclin D1 has unrelated nuclear and cytoplasmic functions.…”

“…Cyclin D1 has been found associated with paxillin at the cell membrane in those migrating cells. Paxillin is also the downstream target of cytoplasmic cyclin D1/CDK4/6 In glioblastoma [64]. Clinical observations support this major role of cytoplasmic cyclin D1 in invasion and metastasis [62,64].…”

“…In normal cells, cyclin D1 is produced in response to extracellular mitogenic signals and the subsequent activation of RAS-dependent signaling cascades, cyclin D1/CDK4/6 complexes assemble, are stabilized and activated ( Figure 1C) [65]. CDK inhibitors of the CIP1/KIP family facilitate cyclin D1/CDK4/6 assembly and nuclear import without inhibiting the kinase activity [64]. Once within the nucleus, D1/CDK4/6 complexes control the G1-to-S phase transition and promote cell cycle progression.…”

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

“…Pharmacological therapy options are limited for both entities, and predictive biomarkers for CDK inhibitors are yet at the beginning of identification. Still, the finding that the Cyclin D1 (CCND1)/CDK4/6-CDKN2A (p16 INK4A )-Rb axis is altered in more than half of HNSCC and GBM cases warrants further investigations [4][5][6][7]. This will hopefully broaden treatment options for patients by applying CDKi's in mono-or combination with chemo-/immunotherapy to prevent resistance.…”