Activation of Akt pathway by transcription-independent mechanisms of retinoic acid promotes survival and invasion in lung cancer cells

Molecular Cancer

Research

Miguel Vargas¹  Claudia Haydée González-De la Rosa²  Alejandro García-Regalado²  Alejandro García-Carrancá³  Elena Aréchaga-Ocampo³ 

[1] Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 14740, México, D. F, Mexico;Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Unidad Cuajimalpa. Artificios 40, Col. Hidalgo, 01120, México, D. F, Mexico;Subdirección de Investigación Básica, Instituto Nacional de Cancerología, San Fernando 22, Col Sección XVI, 14080, México, D. F, Mexico;

关键词: Lung cancer;    ATRA;    Resistance;    PI3k/Akt pathway;    RARs;    RAC;    Cell invasion;    Apoptosis;   

DOI  :  10.1186/1476-4598-12-44

 received in 2013-02-08, accepted in 2013-05-10,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundAll-trans retinoic acid (ATRA) is currently being used in clinical trials for cancer treatment. The use of ATRA is limited because some cancers, such as lung cancer, show resistance to treatment. However, little is known about the molecular mechanisms that regulate resistance to ATRA treatment. Akt is a kinase that plays a key role in cell survival and cell invasion. Akt is often activated in lung cancer, suggesting its participation in resistance to chemotherapy. In this study, we explored the hypothesis that activation of the Akt pathway promotes resistance to ATRA treatment at the inhibition of cell survival and invasion in lung cancer. We aimed to provide guidelines for the proper use of ATRA in clinical trials and to elucidate basic biological mechanisms of resistance.ResultsWe performed experiments using the A549 human lung adenocarcinoma cell line. We found that ATRA treatment promotes PI3k-Akt pathway activation through transcription-independent mechanisms. Interestingly, ATRA treatment induces the translocation of RARα to the plasma membrane, where it colocalizes with Akt. Immunoprecipitation assays showed that ATRA promotes Akt activation mediated by RARα-Akt interaction. Activation of the PI3k-Akt pathway by ATRA promotes invasion through Rac-GTPase, whereas pretreatment with 15e (PI3k inhibitor) or over-expression of the inactive form of Akt blocks ATRA-induced invasion. We also found that treatment with ATRA induces cell survival, which is inhibited by 15e or over-expression of an inactive form of Akt, through a subsequent increase in the levels of the active form of caspase-3. Finally, we showed that over-expression of the active form of Akt significantly decreases expression levels of the tumor suppressors RARβ2 and p53. In contrast, over-expression of the inactive form of Akt restores RARβ2 expression in cells treated with ATRA, indicating that activation of the PI3k-Akt pathway inhibits the expression of ATRA target genes.ConclusionOur results demonstrate that rapid activation of Akt blocks transcription-dependent mechanism of ATRA, promotes invasion and cell survival and confers resistance to retinoic acid treatment in lung cancer cells. These findings provide an incentive for the design and clinical testing of treatment regimens that combine ATRA and PI3k inhibitors for lung cancer treatment.

【 授权许可】

Unknown   
© García-Regalado et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.