Tamoxifen Modulates Protein Kinase C via Oxidative Stress in Estrogen Receptor-negative Breast Cancer Cells

Gundimeda, Usha; Chen, Zhen-Hai; Gopalakrishna, Rayudu

doi:10.1074/jbc.271.23.13504

Cited by 152 publications

(99 citation statements)

References 60 publications

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“…Micromolar concentration of the agents may then cause further inhibition by another mechanism, e.g. involving inhibition of calmodulin activity (MacNeil et al, 1988) or indeed inhibition of protein kinase C (O'Brian et al, 1985;Gundimeda et al, 1996). A further possibility is a heterogeneous population of cells with one subpopulation highly sensitive to inhibition by tamoxifen and N-des and a more resistant subpopulation.…”

Section: Discussionmentioning

confidence: 99%

Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

Dewhurst

Gee²,

Rennie³

et al. 1997

Br J Cancer

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Summary Invasion through stromal extracellular matrix (ECM) is part of the complex, multistep process of tumour cell invasion and metastasis. Our group has previously demonstrated that calcium and calmodulin are important in another step in the metastatic cascadethat of attachment of cells to ECM. Interestingly, the non-steroidal anti-oestrogen tamoxifen (which also has calmodulin antagonist activity), used in the treatment of breast cancer and now in metastatic cutaneous melanoma, can inhibit the attachment of normal and neoplastic cells to ECM. In this study, we investigated whether such drugs, known to inhibit cell attachment, could also subsequently reduce their invasion through a layer of human fibronectin. We examined the ability of the specific calmodulin antagonist J8, tamoxifen and its two major metabolites, N-desmethyltamoxifen (N-des) and 4-hydroxytamoxifen (4-OH), as well as the pure anti-oestrogen ICI 182,780 and 17,Boestradiol to inhibit invasion of the human cutaneous melanoma cell line, A375-SM, uveal melanoma cells and uveal melanocytes. A375-SM cells and uveal melanoma cells showed a high level of invasion (15.2% and 33.7% respectively) compared with melanocytes (around 5%) under the experimental conditions used. Submicromolar concentrations of N-des, tamoxifen, J8 and 1 7,B-oestradiol significantly reduced the invasiveness of the A375-SM cell line. The uveal melanoma cells also showed similar inhibition, although at higher concentrations of these agents. 4-OH and ICI 182, 780 had little or no effect on invasion of A375-SM cells (these were not tested on uveal melanoma cells). All cells used in this study were found to be negative for type nuclear oestrogen receptors, reinforcing the possibility that tamoxifen and 17,-oestradiol can act via mechanisms unrelated to binding to classical oestrogen receptors to inhibit tumour cell invasion.Keywords: melanoma; invasion; calmodulin antagonists; tamoxifen; oestrogen The prognosis for patients with either cutaneous (Garbe et al, 1995) or uveal melanoma (Bedikian et al, 1981;Rajpal et al, 1983) is poor once these tumours have metastasized. Metastatic spread involves several different stages and, in escaping from the primary tumour and in forming distal metastatic deposits, neoplastic cells need to attach to and subsequently invade through stromal ECM (Albini and Colacci, 1993 for review). Metastatic melanoma cells express a greater range of adhesion molecules than their non-transformed precursor, the melanocyte (Mortarini and Anichini, 1993). Initial attachment of cells to ECM proteins then leads to a reorganization of the cell cytoskeleton to form focal adhesions (Van Leeuwen et al, 1994).In recent years, our laboratory has investigated the role of signal transduction systems in the early stages of cell attachment and shown that attachment of melanoma cells to ECM proteins appears to involve intracellular signalling systems, in particular calcium and calmodulin (MacNeil et al, 1992. We also demonstrated that tamoxifen and two of its major metabolites c...

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Section: Discussionmentioning

confidence: 99%

Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

Dewhurst

Gee²,

Rennie³

et al. 1997

Br J Cancer

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“…by mechanisms that are independent of the presence of estrogen receptors (Gundimeda et al, 1996;Treon et al, 1998;. Although in previous in vitro experiments, a series of transformed c-myc/c-H-ras cell lines were found unresponsive to OHT application in culture as determined by growth curves and FACS analysis (Figure 4e,f and data not shown), we investigated the e ect of the highest OHT-concentration on the in vivo growth of MR-1 cells (Figure 6).…”

Section: Activation Of Mad1er Results In Inhibition Of Myc/ras-dependmentioning

confidence: 99%

Repression of in vivo growth of Myc/Ras transformed tumor cells by Mad1

et al. 2002

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The Myc/Max/Mad network of transcriptional regulatory proteins plays an essential role in cell proliferation, growth, apoptosis, and di erentiation. Whereas Myc proteins a ect cell cycle progression positively, Mad proteins are negative regulators of cell proliferation. It has been shown in several in vitro systems that Mad proteins antagonize c-Myc functions. In this report we describe the inhibition of tumor cell outgrowth in vivo by Mad1 expression. Transformed cell lines were generated by co-transfection of c-myc, c-H-ras, and a chimeric mad1ER construct into primary rat embryo cells (MRMad1ER cells). Activation of Mad1 by 4-Hydroxy-Tamoxifen (OHT) resulted in abrogation of telomerase activity, reduced cloning e ciency, and decreased proportion of cells in S phase. Injection of MRMad1ER cells into syngenic rats induced aggressively growing tumors after a short latency period. This tumor growth was inhibited by OHT-treatment of animals, with the extent of inhibition correlating with the amount of OHT injected. No e ect of OHT on tumor growth was observed with similarly transformed Myc/Ras cell lines which did not express Mad1ER. These data demonstrate that Mad1 is able to suppress Myc/Ras-mediated transformation under in vivo conditions.

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“…Tamoxifen works principally through ER antagonism, but also involves ER-independent pathways. Tamoxifen induces apoptosis by increasing oxidative stress, which may mediate its anti-tumor effect [38,39].…”

Section: Discussionmentioning

confidence: 99%

Combination of siRNA-directed gene silencing with epigallocatechin-3-gallate (EGCG) reverses drug resistance in human breast cancer cells

Esmaeili

2015

J Chem Biol

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Elevated expression of NF-E2-related factor 2 (Nrf2), a nuclear transcription factor, is a frequent genetic abnormality seen in this malignancy and is an important contributor to chemoresistance in cancer therapy. In the present study, we investigated if Nrf2 was associated with drug resistance in tamoxifen-resistant MCF-7 (MCF-7/TAM) cells, and whether EGCG, major flavonoid isolated from green tea, could reverse drug resistance in MCF-7/TAM cells. Our results showed that the endogenous expression of Nrf2 as well as its target proteins heme oxygenase-1, NADP (H):quinone oxidoreductase in MCF-7/TAM cells was higher than that in MCF-7 cells. Epicatechin gallate (EGCG) significantly sensitizes MCF-7/TAM cells to tamoxifen and dramatically reduced Nrf2 expression at both the messenger RNA and protein, leading to a reduction of Nrf2-downstream genes. In addition, using siRNA technique, we found that the intracellular Nrf2 protein level was significantly decreased in MCF-7/ TAM cells and tamoxifen resistance was partially reversed by Nrf2 siRNA. Combination of siRNA-directed gene silencing with EGCG downregulated the Nrf2-dependent response and partly reversed tamoxifen resistance in MCF-7/TAM cells in a synergic manner. These results suggested that combining the chemotherapeutic effect of EGCG with siRNA-mediated Nrf2 knock-down results in the feasibility of using Nrf2 inhibitors to increase efficacy of chemotherapeutic drugs.

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Tamoxifen Modulates Protein Kinase C via Oxidative Stress in Estrogen Receptor-negative Breast Cancer Cells

Cited by 152 publications

References 60 publications

Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

Tamoxifen, 17β-oestradiol and the calmodulin antagonist J8 inhibit human melanoma cell invasion through fibronectin

Repression of in vivo growth of Myc/Ras transformed tumor cells by Mad1

Combination of siRNA-directed gene silencing with epigallocatechin-3-gallate (EGCG) reverses drug resistance in human breast cancer cells

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