Abstract 4975: All-trans retinoic acid induces proliferation, survival and migration in A549 lung cancer cells by activating the ERK signaling pathway through a transcription independent mechanism

Abstract

Abstract All-trans retinoic acid (ATRA) have tumor-suppressive capacity by their ability to promote differentiation and inhibit proliferation, mainly in leukemia, however in other tumor types the treatment with ATRA is restricted because not all the patients have the same results. ATRA is able to modulate the PI3K and ERK signaling pathways and promote differentiation in neuronal cells by a transcription independent mechanism. In lung cancer cells this non genomic mechanism by ATRA is able to active the PI3K signaling pathway and trigger cellular processes like invasion and survival. Nevertheless is unknown if ERK could be modulated by ATRA in lung cancer cells. We investigated the effects of ATRA on the activation of ERK pathway in the ATRA-resistant A549 lung adenocarcinoma cell line. The phosphorylated form of ERK was detected by western blot within 5 and 15 min after ATRA treatment. Further evaluation using specific RAR antagonists, AGN 193109 and Ro 41-5253, which prevent expression of ATRA target genes, showed the same effect over ERK. To elucidate the potential crosstalk between PI3K and ERK signaling, we used cells pretreated with wortmannin, a potent and specific PI3K inhibitor, and showed that wortmannin alone or in combination with ATRA increased the activation of ERK. These data suggest that PI3K negatively regulate ERK phosphorylation through the signaling complex ATRA/RARα. As we reported previously, ATRA does not induce significant changes on proliferation, however, the combination of ATRA with PD98059, the pharmacological inhibitor of MEK-ERK, decreases proliferation by 50%. These results suggest that activation of ERK is involved in blocking the classical anti-proliferative effects of ATRA in A549 cell line. Moreover, ERK pathway activation promotes anti-apoptosis in response to ATRA treatment in A549 cells. In addition, wound healing assay in presence of PD98059 showed that migration promoted by ATRA in A549 cells can be delayed. Our results indicate that ATRA activates the ERK signaling pathway by a transcription independent mechanism through signaling cascade, which involves RARα and PI3K modulating the ERK activation. This signaling pathway promotes proliferation, survival and migration in lung cancer cells. The inhibition of ERK signaling pathway restores the anti-tumoral effects of ATRA. It is interesting to speculate that using a combination of ERK and PI3K inhibitors may improve the tumor-suppressive activity of ATRA in lung cancer patients. Note: This abstract was not presented at the meeting. Citation Format: Reyna S. Quintero Barceinas, Alejandro García-Regalado, Elena Aréchaga-Ocampo, Claudia H. González-De la Rosa. All-trans retinoic acid induces proliferation, survival and migration in A549 lung cancer cells by activating the ERK signaling pathway through a transcription independent mechanism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4975. doi:10.1158/1538-7445.AM2015-4975