Cooperation of bcl-2 and myc in the neoplastic transformation of normal rat liver epithelial cells is related to the down-regulation of gap junction-mediated intercellular communication

Deocampo, Nestor D.; Wilson, Melinda R.; Trosko, James E.

doi:10.1093/carcin/21.5.501

Cited by 15 publications

(8 citation statements)

References 49 publications

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“…Although growth in soft agar is often used as a metric for cellular transformation, not all oncogenes are capable of promoting anchorage-independent growth. Notably, over-expression of the bcl-2 oncogene in normal rat epithelial cells (WBF443) and JB6 mouse epidermal cells, does not affect growth rate nor does it allow for anchorage independent growth [35], [36]. We speculate that in the correct cellular context and microenvironment DUSP12's ability to up-regulate c-MET could result in cellular transformation.…”

Section: Discussionmentioning

confidence: 89%

Characterization of a Human Cell Line Stably Over-Expressing the Candidate Oncogene, Dual Specificity Phosphatase 12

2011

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BackgroundAnalysis of chromosomal rearrangements within primary tumors has been influential in the identification of novel oncogenes. Identification of the “driver” gene(s) within cancer-derived amplicons is, however, hampered by the fact that most amplicons contain many gene products. Amplification of 1q21–1q23 is strongly associated with liposarcomas and microarray-based comparative genomic hybridization narrowed down the likely candidate oncogenes to two: the activating transcription factor 6 (atf6) and the dual specificity phosphatase 12 (dusp12). While atf6 is an established transcriptional regulator of the unfolded protein response, the potential role of dusp12 in cancer remains uncharacterized.Methodology/Principal FindingsTo evaluate the oncogenic potential of dusp12, we established stable cell lines that ectopically over-express dusp12 in isolation and determined whether this cell line acquired properties frequently associated with transformed cells. Here, we demonstrate that cells over-expressing dusp12 display increased cell motility and resistance to apoptosis. Additionally, over-expression of dusp12 promoted increased expression of the c-met proto-oncogene and the collagen and laminin receptor intergrin alpha 1 (itga1) which is implicated in metastasis.SignificanceCollectively, these results suggest that dusp12 is oncologically relevant and exposes a potential association between dusp12 and established oncogenes that could be therapeutically targeted.

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Section: Discussionmentioning

confidence: 89%

Characterization of a Human Cell Line Stably Over-Expressing the Candidate Oncogene, Dual Specificity Phosphatase 12

2011

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“…The importance of Bcl‐2 family members in tumorigenesis is well known. Bcl‐2 protein inhibits cell apoptosis and accelerates c‐Myc‐induced tumorigenesis [45]. Furthermore, Bcl‐2 is a direct target gene of c‐Myc and over‐expression of Bcl‐2 has been detected in numerous human cancers including skin, prostate, kidney and bladder [46–49].…”

Section: Discussionmentioning

confidence: 99%

Tumour growth inhibition by an imidazoquinoline is associated with c‐Myc down‐regulation in urothelial cell carcinoma

et al. 2008

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OBJECTIVE To detect and characterize the potential role of c‐Myc in the inhibition of proliferation and induction of cell death of urothelial cell carcinoma by imidazoquinolines, Toll‐like receptor‐7 (TLR7) agonists, that are thought to exert their immunogenic effects through the MyD88/NF‐κB pathway. MATERIALS AND METHODS Human (T24) and murine (MBT‐2) bladder cancer cell lines were cultured in normal culture medium or medium supplemented with imidazoquinoline. The effects of imidazoquinoline on gene expression, transcription and tumorigenesis were then evaluated. Effects of imidazoquinoline on in vivo bladder tumour growth and gene expression were investigated using a mouse model of orthotopic bladder cancer. RESULTS There was a dose‐dependent decrease in c‐Myc expression in bladder cancer cells treated with imidazoquinoline; the transcriptional activity of c‐Myc was also significantly reduced. Furthermore, the in vitro proliferation and tumorigenesis of MBT‐2 cells were suppressed in a dose‐dependent manner. For in vivo experiments, a third of mice with bladder cancer treated with intravesical imidazoquinoline showed evidence of residual bladder tumour, vs all the placebo‐treated mice. In vivo expression of c‐Myc, cyclin D2 and proliferating cell nuclear antigen in the bladder tumour tissue were also down‐regulated. CONCLUSIONS Imidazoquinolines can inhibit c‐Myc expression and directly affect cell growth and tumorigenesis of bladder cancer cells, independent of an immune response. These direct effects might be synergistic with previously described immunogenic actions of imidazoquinolines. Our findings could broaden the potential application of imidazoquinoline therapy beyond dermatological malignancies, and further clinical studies are warranted.

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“…When C-myc, which is overexpressed in $30% of breast cancer and essential for cell cycling [Koskinen and Alitalo, 1993], and bcl-2, one of the major genes implicated in the regulation of apoptosis [Reed, 1994], are overexpressed, they have been described to confer tumor chemoresistance, resulting in an unfavorable prognosis [Fanidi et al, 1992]. Together, the myc-oncogene and the protooncogene bcl-2 have been found to cooperate in the neoplastic transformation of normal rat liver epithelial cells, and this effect was related to GJIC downregulation [DeoCampo et al, 2000]. Retinoids and Tx have been independently studied for their ability to regulate c-myc [Kang et al, 1996;Shang et al, 1998] and bcl-2 expression [Toma et al, 1997;Zhang et al, 1999].…”

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confidence: 99%

Increased gap junctional intercellular communication is directly related to the anti‐tumor effect of all‐trans‐retinoic acid plus tamoxifen in a human mammary cancer cell line

Sáez

Velásquez

Montoya

et al. 2003

J of Cellular Biochemistry

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Additive effects against tumor cells might be achieved by combining anti-neoplastic agents directed against one or more altered mechanisms in cancer. We investigated the participation of gap junctional intercellular communication (GJIC), which is commonly dysfunctional in tumor cells as a possible mediating mechanism of the effect of all-trans-retinoic acid (RA) and tamoxifen (Tx) in MCF-7 human breast cancer cell lines. The combination of RA + Tx stimulated GJIC in approximately 53 +/- 3% of MCF-7 cells as early as after 6 h of treatment remaining communicated through 144 h of culture. The GJIC enhancement occurred along with immunolocalization of Cx26 and 43 at the membrane of contacting cells and correlated with higher protein levels. Cx40 immunoreactive plaques were detected at cell-to-cell contacts during 48 h of RA + Tx treatment that did not involve higher protein expression, to the contrary, a downregulation occurred after 72 h of treatment. Cell proliferation inhibition upon RA + Tx exposure was observed with optimal effects at 96-120 h of culture with an accumulation of cells primarily in G2/M and G0/G1 cell cycle boundaries. An enhancement of the pre-existing E-cadherin levels was observed after drug exposure along with a downregulation of Bcl-2 and C-myc protein levels and a reduction of telomerase activity, suggesting partial tumor phenotype reversion. Blockage of the RA + Tx-induced GJIC with 18-beta-glycyrrhetinic acid (beta-Gly) prevented in 34% the inhibition of MCF-7 proliferation and the E-cadherin increment in 30% at 96 h of culture. GJIC blockage did not alter the downregulation of Bcl-2, c-Myc, or telomerase activity induced by RA + Tx. Our results showed the participation of GJIC as a mediator mechanism of the combined action of RA and Tx in MCF-7 cells. The chemopreventive modulation of GJIC might represent an approachable alternative for the improvement of cancer therapy.

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Cooperation of bcl-2 and myc in the neoplastic transformation of normal rat liver epithelial cells is related to the down-regulation of gap junction-mediated intercellular communication

Cited by 15 publications

References 49 publications

Characterization of a Human Cell Line Stably Over-Expressing the Candidate Oncogene, Dual Specificity Phosphatase 12

Characterization of a Human Cell Line Stably Over-Expressing the Candidate Oncogene, Dual Specificity Phosphatase 12

Tumour growth inhibition by an imidazoquinoline is associated with c‐Myc down‐regulation in urothelial cell carcinoma

Increased gap junctional intercellular communication is directly related to the anti‐tumor effect of all‐trans‐retinoic acid plus tamoxifen in a human mammary cancer cell line

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