Overexpression of cdk4/cyclin D1, a possible mediator of apoptosis and an indicator of prognosis in human primary lung carcinoma

Abstract

The relation between expression of cell cycle-regulator molecules and apoptosis was examined in surgical specimens and cultured human lung carcinoma cell lines. Cell-cycle regulation, a fundamental mechanism determining cell proliferation, is precisely regulated by the specific interaction of cyclins, cdks and cdk-inhibitors. 1,2 Aberrant expression of cyclins and cdks is involved in oncogenic transformation in cultured cells. 3,4 Successive clinicopathologic analyses of human malignant tumors, including carcinomas of the breast, lung, gastrointestinal tract, ovary and other sites, showed a correlation between overexpression of cell-cycle proteins and worse clinical outcome. [5][6][7][8][9] Indeed, in previous studies of human lung carcinomas and soft tissue sarcomas, we found that the expression and kinase activity of the cyclin A/cdk2 complex were novel predictors of proliferative activity and prognosis. 6,10,11 Thus, studies in both cultured cells and human tumors have consistently suggested that dysregulated expression of cyclin/cdk complexes is crucially involved in neoplastic transformation and the aggressive phenotypes of cancers.However, in the past decade, overexpression or abnormal expression of several positive regulators of the cell cycle has been closely associated with apoptosis. These proteins include c-myc, E2F1 and the HPV oncoproteins. 12-15 Several studies have implicated cell-cycle regulator molecules in apoptosis: e.g., upregulation of cyclin D1, cdk4 and/or cdc2 may be a critical event during apoptosis in neuronal cells. 16 -18 Furthermore, several reports have implicated other cell cycle-regulatory molecules, including cyclin E and cyclin B, as key factors in the apoptosis of cultured cells. 19,20 Although these reports suggested that overexpression of any cyclin or cdk could induce apoptosis, each has been shown to have individual potential functions. Previously, we demonstrated that (i) constitutive overexpression of cdk4 significantly promotes apoptosis in rat pheochromocytoma PC12 cells; 17 (ii) in contrast, constitutive overexpression of cdk2 or cdc2 promotes cell proliferation and abrogates the response to nerve growth factor; 4,21 and (iii) transient overexpression of cdk4 or cyclin D1 induces apoptosis in the presence of trophic support in neuronal, hematopoietic and human cancer cell lines. 22,23 These results overall suggest that cdk4/cyclin D1 kinase plays a specific and crucial role in inducing apoptosis in a wide spectrum of cell types. However, observations of these phenomena have been limited to cultured cells and precise pathobiologic or clinicopathologic analyses on apoptosis in surgical specimens of human tumors have not been documented. Several clinicopathologic analyses of apoptosis have examined its prognostic significance in human cancers but with somewhat mixed results. In lung carcinomas, several groups have reported that enhanced apoptosis is associated with shortened survival, 24,25 yet other studies have found no statistically significant correlation. 26 In cont...

Cell cycle and apoptosis regulatory gene expression in the bone marrow of patients with de novo myelodysplastic syndromes (MDS)

“…CDK2 is induced after treatment with HIV-1 Tat [34]. In apoptotic thymocytes, CDK2 activation is required for cell death and only occurs subsequent to bax expression or bcl2 repression [40]. In addition, upregulation of CDK4 may be a primary and critical factor in induction of apoptosis in human lung carcinomas in vivo [41].…”

Marine steroids as potential anticancer drug candidates: In silico investigation in search of inhibitors of Bcl-2 and CDK-4/Cyclin D1

“…1b). Perturbation of CDK-4/Cyclin D1 pathways in diverse 70 tumors types elucidates that various oncogenic transformations 71 are addicted to high level of CDK4 activity [9][10][11][12]. Active role of 72 CDK4 is a key factor in initiation and development of tumors in 73 cancer and it has been found that its suppression leads to the acti-74 vation of p21 (P2 folds), a tumor suppressor that checks cell pro-75 liferation and migration [13].…”

Translational Oncogenomics and Human Cancer Interactomics: Advanced Techniques and Complex System Dynamic Approaches

“…One such family of pathways contains the cell cyclins. Cyclins are often overexpressed in cancerous cells (Dobashi et al 2004). Our novel theoretical analysis based on recently published studies of cyclin signaling, with special emphasis placed on the roles of cyclins D1 and E, suggests novel clinical trials and rational therapies of cancer through re-establishment of cell cycling inhibition in metastatic cancer cells.…”