Abstract
Oxaliplatin is a major treatment for metastatic colorectal cancer, however its effectiveness is greatly diminished by the development of resistances. Our previous work has shown that oxaliplatin efficacy depends on the reactive oxygen species (ROS) produced by Nox1. In this report, we investigated Nox1 involvement in the survival mechanisms of oxaliplatin resistant cell lines that we have selected. Our results show that basal ROS production by Nox1 is increased in resistant cells. Whereas the transitory Nox1-dependent production of superoxide contributes to the cytotoxicity of oxaliplatin in sensitive cells, oxaliplatin treatment of resistant cells leads to a decrease in the production of superoxide associated with an increase of H2O2 and a decreased cytotoxicity of oxaliplatin. We have shown that calpains regulate differently Nox1 according to the sensitivity of the cells to oxaliplatin. In sensitive cells, calpains inhibit Nox1 by cleaving NoxA1 leading to a transient ROS production necessary for oxaliplatin cytotoxic effects. In contrast, in resistant cells calpain activation is associated with an increase of Nox1 activity through Src kinases, inducing a strong and maintained ROS production responsible for cell survival. Using a kinomic study we have shown that this overactivation of Nox1 results in an increase of p38 MAPK activity allowing the resistant cells to escape apoptosis. Our results show that the modulation of Nox1 activity in the context of anticancer treatment remains complex. However, a strategy to maximize Nox1 activation while inhibiting the p38 MAPK-dependent escape routes appears to be an option of choice to optimize oxaliplatin efficiency.
Highlights
Colorectal cancer (CRC) became a major cancer due to its increasing frequency and its mortality
The IC50 of oxaliplatin is 0.8 ± 0.2 μM for HT29-D4 cells compared www.impactjournals.com/oncotarget to 5.2 ± 0.6 μM for Rox1 and 6.3 ± 0.9 μM for Rox2 cells (p
The kinases of the p38 MAPK family were in the top list with high specificity scores (2.7 for p38α MAPK (MAPK 14), 1.9 for p38γ MAPK (MAPK12) and 1.4 for p38δ MAPK (MAPK 11)) and high normalized kinase statistics (1.5, 1.5 and 1.3 for p38α MAPK, p38γ MAPK and p38δ MAPK, respectively; Figure 6B). These results show that p38 MAPK are activated by oxaliplatin in our resistant cells. p38 MAPK is well known to be strongly implicated in cell survival, notably in response to chemotherapy
Summary
Colorectal cancer (CRC) became a major cancer due to its increasing frequency and its mortality. A quarter of the patients are diagnosed at the metastatic stage and 50% will develop metastasis [2]. At this stage, the survival rate is only 13.1% in the USA (National Cancer Institute) and less than 10% in Europe (6.6% in England, National Cancer Intelligence Network, 2009, and 8.1% in France, Institut National du Cancer, 2012). CRC is usually treated with multidrug chemotherapies, such as FOLFIRI and FOLFOX regimens. These first-line treatments, constituted of 5-fluorouracil (5-FU), folinic acid and irinotecan or oxaliplatin (L-OHP), have equivalent efficacies which remain low due to the therapeutic escape of tumor cells. It is critical to identify the actors of these resistances, to oxaliplatin, to improve the treatment efficiency and to predict the tumor cell response
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