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

Abstract

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.

Tissue Stiffness and Hypoxia Modulate the Integrin-Linked Kinase ILK to Control Breast Cancer Stem-like Cells

“…Previous work has suggested that ILK regulates cell survival through the PI3K/Akt pathway (32), which has also been implicated in cancer cell (33,34) and CSC survival (35,36), cancer cell proliferation (37,38), and the CSC phenotype (39). We found that knockdown of ILK reduced the phosphorylation of Akt (Figure 4A; Figure S4).…”

“…ILK is well appreciated for its roles in stemness and metastasis (33,34,37) and is known to stimulate tumor angiogenesis through VEGF-A (51). Our data suggest a positive feedback loop in which the signaling activated by ILK induces increased expression of mechanosensors, including β1-integrin and ILK itself.…”

Activation of Notch1 inhibits medial edge epithelium apoptosis in all-trans retinoic acid-induced cleft palate in mice

“…It has been reported that atRA treatment may inhibit the proliferation of glioma cells [19] and mouse embryonic palatal mesenchymal cells [16,17]. atRA-induced proliferation and survival has also been assessed in lung cancer cells [20,21], chicken primordial germ cells and neuronal cells [22]. Investigations of the histopathological effects of retinoic acid on embryonic structure and adult tissues were conducted and revealed that the effect of atRA varies among different tissue organization types [23].…”

Therapeutically Targeting Epigenetic Regulation of Cancer Stem Cells

“…As such, forcing differentiation upon CSCs has attracted considerable attention as a potential anticancer therapy. For example, lung cancer has been shown to be resistant to ATRA treatment, which results in cancer cell promotion [79]. In culture, ATRA readily forces hESCs and hEC cells into a neural differentiation lineage, which is characterized by loss of stemness properties including tumorigenicity.…”