Increased expression of cyclin B1 sensitizes prostate cancer cells to apoptosis induced by chemotherapy

Abstract

Chemotherapeutic drugs ideally should take advantage of the differences between transformed and normal cells and induce apoptosis only in cancer cells. One such difference may be the overexpression of cyclin B1 protein in cancer cells, which is required for the proper progression through mitosis. Previously, we showed that treatment of human prostate cancer cells with 2-methoxyestradiol (2-ME) or docetaxel results in an accumulation of cyclin B1 protein and an increase in cyclin B1 kinase activity, followed by induction of apoptotic cell death. Inhibition of cyclin B1 kinase lowers apoptosis induced by 2-ME and docetaxel. In this study, we established a positive correlation between cyclin B1 protein and apoptosis induced by chemotherapy in prostate cancer cells. There is minimal cyclin B1 and induction of apoptosis by chemotherapy in nontransformed cells. LNCaP and PC-3 prostate cancer cells stably overexpressing cyclin B1 are more sensitive to apoptosis induced by chemotherapy. LNCaP cells expressing cyclin B1 small interfering RNA to lower cyclin B1 protein or dominant negative cyclin-dependent kinase 1 to inhibit cyclin B1 kinase show a decrease in apoptosis. Increased sensitivity to apoptosis by overexpression of cyclin B1 may be due to lower Bcl-2, higher p53, and decreased neuroendocrine differentiation. We suggest that a cancer-specific mechanism whereby 2-ME and docetaxel may exert anti -prostate cancer activity is the deregulated activation of cyclin B1 kinase, leading to the induction of apoptotic cell death. Our results also suggest that higher levels of cyclin B1 in prostate cancer cells may be a good prognostic marker for chemotherapy. [Mol Cancer Ther 2007;6(5):1534 -43]

Evaluation of Schistosome Promoter Expression for Transgenesis and Genetic Analysis

“…However, strong overexpression of the SmActin1, SmCyclinB, SmCaspase3 or SmCaspase7 genes from the SmActin1 promoter, induced mortality in schistosomula. This correlates with what is generally reported in other systems [40], [48]–[55], [63], although in some cases, gene overexpression causes morphological and developmental changes, as observed in human myoblast cells and esophageal squamous cell carcinoma [39], [40], [42]. The overexpression of each of these genes in schistosomula may alter schistosome early development and be the primary cause of the schistosome lethality observed.…”

Molecular phenotyping of circulating tumour cells in patients with prostate cancer: prediction of distant metastases

“…The AR has been reported to regulate cellular proliferation by control of CDK and cyclins at the transcriptional level and by posttranslational modifi cations that infl uence cell cycle protein activity, including overexpression of cyclin B in recurrent tumours [ 14 ] . A further facet of cyclin B overexpression has been reported, namely, to sensitize malignant prostate cells to apoptosis induced by chemotherapy [ 15 ] . BFGF has been reported to have several functions in advanced PCa.…”

Enhancing Therapeutic Cellular Prostate Cancer Vaccines

“…Also our findings add to recent data suggesting that in CaP, tumor-associated hypoxia associates to malignant progression, metastasis, resistance to Figure 3A) were associated with Gleason score and disease prognosis ( Figure 3B). Since the products of CCNB1 (Gomez, de Las Pozas et al 2007) and HMMR (Gust, Hofer et al 2009) genes have been recently identified as molecular markers of CaP progression, our results suggest the potential utility of hypoxia-associated genes as a criterion to identify CaP biomarkers with prognostic value. In additional studies we found a high correlation between DLG7 and DNA topoisomerase 2α (TOP2A) transcript levels (Pearson Coefficient= 0.816) ( Figure 3C (Koffa, Casanova et al 2006).…”

“…Since the products of CCNB1 (Gomez, de Las Pozas et al 2007) and HMMR (Gust, Hofer et al 2009) genes have been recently identified as molecular markers of CaP progression, our results suggest the potential utility of hypoxia-associated genes as a criterion to identify CaP biomarkers with prognostic value. In additional studies we found a high correlation between DLG7 and DNA topoisomerase 2α (TOP2A) transcript levels (Pearson Coefficient= 0.816) ( Figure 3C).…”