Knockdown of CDK6 enhances glioma sensitivity to chemotherapy

Abstract

Abstract. Chemotherapy is widely used for the treatment of glioma. Given the high resistance of brain neoplasm tissues to chemotherapy, it is important to find new methods to improve the effects of chemotherapy. However, the molecular mechanisms underlying glioma resistance to chemotherapy are largely unknown. Here, we demonstrate that CDK6, a cell cycle regulator, is significantly upregulated in glioma cells, and the increasing expression of CDK6 correlates well with the grades of glioma malignancy. Using shRNA-mediated CDK6 knockdown, we found that the proliferation and survival of tumor cells were dramatically inhibited. Moreover, CDK6 knockdown in the U251 glioma cell line caused significant increase in the apoptosis of U251 cells treated with temozolomide (TMZ). Furthermore, CDK6 knockdown reduced the expression level of drug resistance genes such as MRP and MDR. These data indicate that CDK6 is an important mediator of glioma resistance to chemotherapy. Our findings provide a new strategy for the development of chemotherapy sensitizer. IntroductionGlioma is the most common tumor of the brain and accounts for 45-55% of all brain tumors. Based on histological features (nuclear atypia, mitosis, microvascular enrichment and necrosis) and malignancy, glioma is classified into four grades (1). Grade 1 is innocent and curable with surgical resection; grade 2 is a low grade diffuse glioma and can progress into higher grades; grade 3 and 4 gliomas are malignant and have increased capability to proliferate and invade. The grade 4 glioma, glioblastoma multiforme (GBM), is the most aggressive.Surgical resection is the primary therapy to treat glioma (2). However, surgical removal is very restrictive, thus it is difficult to completely remove diffusive tumor tissues, especially higher grade gliomas. These glioma tissues invade into the white matter or diffuse along the ventricle surface, so other strategies such as chemotherapy are very important to remove cancer cells as completely as possible (3-5). Chemotherapy increases the life of GBM patients. Clinical statistics reveals that, chemotherapy treatment leads to a 15% reduction of mortality, and a 6% increase of 1-more year survival. However, the effect of chemotherapy on glioma is not satisfactory, largely due to three problems. The first problem is the diagnosis of diffusive glioma tissues, which are tiny and grow deep in the brain tissue and are hard to access. The second problem is the blockade of chemotherapy drug by the blood-brain barrier. The third problem is that glioma is highly tolerant under chemotherapy treatment. Understanding the fundamentals, especially the molecular mechanisms, is critical to increase the susceptibility of glioma to chemotherapy.Tumor cells originated from cells with abnormal proliferation and dysregulation of the cell cycle (6,7). Molecular profiling studies showed that the genes controlling cell growth and restricting cell division are silenced, and genes promoting cell proliferation and facilitating cell cycle are overexpressed. M...

Progranulin Deficiency Reduces CDK4/6/pRb Activation and Survival of Human Neuroblastoma SH-SY5Y Cells

“…The effects of these two drugs on survival of SH-SY5Y cells are in consonance with the reported effect of PD332991 on myeloma, increasing the cell sensitivity to bortezomib-induced apoptosis [41] and with the observation that knockdown of CDK6 enhanced the susceptibility of glioma cells to chemotherapy [42]. The fact that these drugs did not affect survival of PGRN-deficient cells, suggest a threshold for CDK4/6-associated kinase [43].…”

Restoring the oncosuppressor activity of microRNA-34a in glioblastoma using a polyglycerol-based polyplex

“…It has been found to be aberrantly activated in human cancers via mutation, amplification or protein overexpression 50 . CDK6, a cell cycle regulator, is significantly upregulated in glioma cells, and its elevated expression correlates well with the grade of glioma malignancy 51 . CDK6 knockdown dramatically inhibits proliferation and survival of tumor cells and reduces the expression level of drug resistance genes such as Multidrug Resistance (MDR) and Multidrug Resistance associated Protein (MRP) 51 .…”

“…CDK6, a cell cycle regulator, is significantly upregulated in glioma cells, and its elevated expression correlates well with the grade of glioma malignancy 51 . CDK6 knockdown dramatically inhibits proliferation and survival of tumor cells and reduces the expression level of drug resistance genes such as Multidrug Resistance (MDR) and Multidrug Resistance associated Protein (MRP) 51 . The Notch signaling pathway is involved in cell fate decisions during normal development and in the generation of several cancers 52 .…”

Assessment of citalopram and escitalopram on neuroblastoma cell lines: Cell toxicity and gene modulation

“…Interestingly, CDK6 and IGF1 were down-regulated only by citalopram. Up-regulation of CDK6 might be correlated with the malignancy of glioma, promoting both its proliferative and invasive capabilities [55, 56]. In addition CDK6 activates transcription factor E2F1/2 that might activate several drug-resistant genes which are up-regulated in glioma cells [57, 58].…”

“…These data have suggested CDK6 might constitute a therapeutic target for malignant gliomas. In vitro , inhibitors of CDK6 have been shown to enhance the sensitivity to chemotherapy on glioma cell lines [56]. They induce cell-cycle arrest and senescence in human neuroblastoma cell lines [59].…”