Inhibition of JNK reduces G2/M transit independent of p53, leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells

Abstract

c-Jun N-terminal kinase (JNK) is activated by diverse cell stimuli, including stress, growth factors, and cytokines. Traditionally, activation of JNK by stress treatment is thought to induce cell death. However, our recent data indicate that JNK's ability to sensitize cells to apoptosis may be, in part, cell cycle dependent. Here, we show that the majority of both paclitaxel-and UV-induced apoptosis can be inhibited by the pharmacological JNK inhibitor, SP600125, in MCF-7 cells. However, inhibition of JNK does little to reverse doxorubicin-induced apoptosis in MCF-7 cells or doxorubicin-and UV-mediated death in MDA MB-231 cells. SP treatment causes G2/M arrest of three breast cancer cell lines and results in the endoreduplication (cellular DNA content 44N) of MCF-7 and MDA MB-231 cells. These effects on cell cycle and apoptosis are not significantly altered by the inhibition of p53, indicating that JNK is functioning independently of p53. Lastly, inhibition of JNK using both SP and antisense oligonucleotides targeted to JNK1 and JNK2 reduced proliferation of all three breast cancer cell lines. Taken together, these results suggest that the activation of JNK is important for the induction of apoptosis following stresses that function at different cell cycle phases, and that basal JNK activity is necessary to promote proliferation and maintain diploidy in breast cancer cells.

Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways

“…These findings were also supported by the results of the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase biotin-dUPT nick end labeling (TUNEL) assays (data not shown). Although SP600125 has been shown to prolong mitotic progression (Du et al, 2004) and cause G2/M arrest (Mingo-Sion et al, 2004), we identified that 10 mM SP 600125 did not significantly interfere with paclitaxel-induced cell cycle profile change (Figure 2c and d). Nonetheless, 20 mM SP 600125 did change the cell cycle profiles (data not shown).…”

“…In addition to its stabilizing effects on the microtubules and the subsequent cell cycle arrest in the G2-M phase, paclitaxel also induces the vast activation of signal-transduction pathways that may be associated with proapoptotic signaling (Blagosklonny and Fojo, 1999;Taxman et al, 2003). Among the proapoptotic signaling networks activated by paclitaxel (Meikrantz and Schlegel, 1996;Lee et al, 1997), the c-Jun Nterminal kinase (JNK) signaling pathway played an important role (Lee et al, 1998;Wang et al, 1999Wang et al, , 2000MacKeigan et al, 2000;Vivat-Hannah et al, 2001;Mingo-Sion et al, 2004).…”

Effect of quercetin derivatives on melanogenesis stimulation of melanoma cells

“…ERK phosphorylates more than 160 proteins, including transcription factors, enzymes, protein kinase relating to signal transduction, and so on, and it ultimately down regulates the expression of MITF and melanogenesis [27][28][29][30]. JNK, involved in proliferation and apoptosis cancer cells, also controls the melanogenesis by downregulating the expression of MITF [31][32][33].…”

Regulation of MAP Kinases by the VHR Dual-Specific Phosphatase – Implications for Cell Growth and Differentiation

“…Depending on the particular cell type, cell-cycle arrest is accompanied by increasing DNA accumulation or by cell death. 16,76,77 This mechanism may be responsible for the anti-cancer activity of several natural compounds with anti-JNK activity. 80,81 Interestingly, mouse embryonic fibroblasts derived from JNK1 -/-and JNK2 -/-mice revealed that these two kinases have somewhat different roles in cell cycle regulation: JNK2 -/-cells exhibit a shorter G 1 cell cycle phase, i.e., they enter S phase earlier than wild-type counterparts, while JNK1 -/-cells show the inverse phenotype, a longer G 1 phase than wild-type cells.…”