trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin

This study is about trans-Fatty acids (TFAs) these are food-derived fatty acids associated with various diseases including cardiovascular diseases. However, the underlying etiology is poorly understood. Here, we show a pro-apoptotic mechanism of TFAs such as elaidic acid (EA), in response to DNA interstrand crosslinks (ICLs) induced by cisplatin (CDDP). We previously reported that TFAs promote apoptosis induced by doxorubicin (Dox), a double strand break (DSB)-inducing agent, via a non-canonical apoptotic pathway independent of tumor suppressor p53 and apoptosis signal-regulating kinase (ASK1), a reactive oxygen species (ROS)-responsive kinase. However, here we found that in the case of CDDP-induced apoptosis, EA-mediated pro-apoptotic action was reversed by knockout of either p53 or ASK1, despite no increase in p53 apoptotic activity. Upon CDDP treatment, EA predominantly enhanced ROS generation, ASK1-p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway activation, and ultimately cell death, all of which were suppressed either by co-treatment of the NADPH oxidase (Nox) inhibitor Apocynin, or by knocking out its regulatory protein, receptor-interacting protein 1 (RIP1).

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Fig:  Major industrial TFAs promote CDDP-induced apoptosis. (a) U2OS cells were pretreated with or without 200 μM EA for 12 h, and then stimulated with various concentrations of CDDP for 24 h, subjected to cell viability assay. Data shown are the mean ± SD (n = 3). (b) U2OS cells were pretreated with the indicated concentrations of OA or EA for 12 h, and then stimulated with or without 40 μM CDDP for 24 h, subjected to cell viability assay. Data shown are the mean ± SD (n = 3). (c) U2OS cells were pretreated with or without 200 µM EA for 12 h, and then stimulated with 40 μM CDDP for the indicated time periods. Cell lysates were subjected to immunoblotting with the indicated antibodies. *, non-specific band. (d) U2OS cells were pretreated with or without 200 µM EA for 11.5 h, treated with the pan-caspase inhibitor z-VAD-fmk for 0.5 h, and followed by stimulation with 40 μM CDDP for 24 h, subjected to cell viability assay. Data shown are the mean ± SD (n = 3). (e and f) U2OS cells were pretreated with the indicated fatty acids at 200 μM for 12 h, and then stimulated with 40 μM CDDP for 24 h, subjected to cell viability assay. Data shown are the mean ± SD. NS, not significant; **p < 0.01; ***p < 0.001 (vs. cells without any fatty acid); †††p < 0.001.

These results demonstrate that in response to CDDP ICLs, TFAs promote p53-dependent apoptosis through the enhancement of the Nox-RIP1-ASK1-MAPK pathway activation, providing insight into the diverse pathogenetic mechanisms of TFAs according to the types of DNA damage.

Hirata, Y., Takahashi, M., Yamada, Y. et al. trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin-induced DNA interstrand crosslinks via the Nox-RIP1-ASK1-MAPK pathway. Sci Rep 11, 10350 (2021). https://doi.org/10.1038/s41598-021-89506-8

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