Inducible overexpression of c-Jun in MCF7 cells causes resistance to vinblastine via inhibition of drug-induced apoptosis and senescence at a step subsequent to mitotic arrest

Abstract

Abstractc-Jun is a major component of the AP-1 transcription factor and plays a key role in regulation of diverse biological processes including proliferation and apoptosis. Treatment of a wide variety of cells with the microtubule inhibitor vinblastine leads to a robust increase in c-Jun expression, JNKmediated c-Jun phosphorylation, and activation of AP-1-dependent transcription. However, the role of c-Jun induction in the response of cells to vinblastine remains obscure. In this study we used MCF7 breast cancer cell lines that express the dominant-negative form of c-Jun, TAM-67, as well as cells that overexpress c-Jun, under the control of an inducible promoter. Vinblastine induced c-Jun protein expression, c-Jun phosphorylation, and AP-1 activation in MCF7 cells, and these parameters were strongly inhibited by inducible TAM-67 expression and strongly enhanced by inducible c-Jun expression. Vinblastine-induced cell death was not affected by TAM-67 expression whereas cells were protected by c-Jun overexpression. Further investigation revealed that apoptotic and senescent cells were observed after vinblastine treatment and that both outcomes were strongly inhibited by cJun overexpression. Although c-Jun expression inhibited cell death, it did not affect the ability of vinblastine to induce mitotic arrest. These results indicate that c-Jun expression plays a protective role in the cellular response to vinblastine and operates post-mitotic block to inhibit drug-induced apoptosis and senescence.

c‐Jun blocks cell differentiation but not growth inhibition or apoptosis of chronic myelogenous leukemia cells induced by STI571 and by histone deacetylase inhibitors

“…Contrary to those observations, Poindessous-Jazat et al (2002) also showed that c-Jun overexpression inhibited serum deprivation-induced apoptosis in these cells. In addition, the studies of apoptosis induced in other cell types have implicated c-Jun protects cells against serum deprivation-induced or anticancer drug-induced cell death (Huang et al, 2000;Duan et al, 2007). These results suggest that c-Jun does not affect apoptosis or may function to modulate apoptosis either positively or negatively, depending on the microenvironment and the cell type.…”

Novel roles of prolactin and estrogens in breast cancer: resistance to chemotherapy

“…Vinblastine also interferes with amino acid, cAMP, and glutathione metabolism, and can induce apoptosis through the nuclear factor kB/inhibitor of kB (NF-kB/IkB) pathway (Huang et al 2004). Apparently, c-Jun protects T47D cells from vinblastine-induced cell death, although it does not prevent the mitotic block (Duan et al 2007). At nontoxic doses, vinblastine inhibits chemotaxis and endothelial cell proliferation, highlighting its antiangiogenic properties (Vacca et al 1999).…”

Induction of Apoptosis by Vinblastine via c-Jun Autoamplification and p53-Independent Down-Regulation of p21WAF1/CIP1

“…For example, whereas a dominant-negative to c-Jun rendered KB-3 cells more vinblastine-resistant , suggesting a proapoptotic role, c-Jun knockout fibroblasts, predicted to be more resistant, were equally as sensitive as wild-type cells (Obey et al, 2005). In addition, stable or inducible overexpression of c-Jun renders cells markedly resistant to vinblastine (Obey et al, 2005;Duan et al, 2007). These results may reflect cell type-specific differences in c-Jun function and probably reflect the fact that c-Jun plays a role in both cell proliferation and cell death and can functionally participate in many different protein complexes.…”