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.

Reyna Sara Quintero Barceinas,Alejandro García-Regalado,Nicolás Villegas-Sepúlveda,Elena Aréchaga-Ocampo,Claudia Haydée González-De La Rosa

doi:10.1155/2015/404368

Abstract

All-trans retinoic acid (ATRA) has been used as an antineoplastic because of its ability to promote proliferation, inhibition, and differentiation, primarily in leukemia; however, in other types of cancer, such as lung cancer, treatment with ATRA is restricted because not all the patients experience the same results. The ERK signaling pathway is dysregulated in cancer cells, including lung cancer, and this dysregulation promotes proliferation and cell invasion. In this study, we demonstrate that treatment with ATRA can activate the ERK signaling pathway by a transcription-independent mechanism through a signaling cascade that involves RARα and PI3K, promoting growth, survival, and migration in lung cancer cells. Until now, this mechanism was unknown in lung cancer cells. The inhibition of the ERK signaling pathway restores the beneficial effects of ATRA, reduces proliferation, increases apoptosis, and blocks the cell migration process in lung cancer cells. In conclusion, our results suggest that the combination of ATRA with ERK inhibitor in clinical trials for lung cancer is warranted.

Highlights

Lung cancer is the second most common cancer and is the leading cause of cancer mortality worldwide for both men and women [1]
We investigated the effects of All-trans retinoic acid (ATRA) on the regulation of the ERK pathway at different times in the ATRAresistant A549 cell line
The results show that pretreatment with the inhibitors and treatment with ATRA for 15 minutes did not prevent ERK activation (Figure 2), which confirms that the activation of ERK is a transcription-independent mechanism

Summary

Introduction

Lung cancer is the second most common cancer and is the leading cause of cancer mortality worldwide for both men and women [1]. New treatments with novel action mechanisms have been explored for advanced lung cancer, including retinoid administration [4]. All-trans retinoic acid (ATRA) is a retinoid and a promising agent in the treatment of cancer due to its ability to inhibit proliferation and induce apoptosis in many in vivo and in vitro assays on tumor cells [5]. The biological effects of ATRA are achieved through binding to RAR nuclear receptors [7]. RAR can form heterodimers with other nuclear receptor types including RXR; this association is needed to enable

Methods

Results

Conclusion