Akt/mTOR Activation in Lung Cancer Tumorigenic Regulators and Their Potential Value as Biomarkers

Abstract

The high incidence and modest therapeutic outcomes of lung cancer have prompted the identification of cell molecular targets/biomarkers within the complex networks of interactions involved in cell malignancy. Most of the EMT-related regulatory mediators underline patients’ biologic variations, therapeutic refractory events, and tumor cell heterogeneity. Patient stratification based on the understanding of the relevant pathways, such as the PI3K/Akt axis crucial in EMT initiation, could favorably alter disease management. Significant clinical advantage could be expected when overexpressed Akt tyrosine kinase (Akt2) is addressed as a malignant biomarker to guide clinical management decisions, improving prognosis in lung cancer patients. Moreover, one should not miss the opportunity of using it as a druggable target aiming at the inhibition of the downstream complexity that underlies cell proliferation and survival, expression of stemness markers and drug resistance. The value of mTOR, as a downstream target of Akt, and the further activation of EMT transcription factors Twist, Snail and Zeb1 are revisited in this review. An in-depth state-of-the-art assessment provides evidence of its role in the mechanistic inhibition of epithelial markers, such as E-cadherin and miR-200, while inducing the expression of the mesenchymal ones, such as vimentin, N-cadherin, and miR-21. Lastly, evidence suggesting another transcription factor, FOXM1, as the link between the PI3K/Akt and Wnt/β-catenin pathways, prompting cell metabolism through the regulation of p70S6K, is analyzed. A more realistic approach is advised to address unmet clinical needs and support decision making at a clinical level. Taking into consideration several complex intracellular interactions might further improve patient stratification and result in better outcomes.

Shrimp Lipids Inhibit Migration, Epithelial–Mesenchymal Transition, and Cancer Stem Cells via Akt/mTOR/c-Myc Pathway Suppression

“…Studies have shown that inhibiting Akt signaling can lead to the downregulation of Sox2 expression and the depletion of lung CSCs in NSCLC [16]. Similarly, the suppression of mTOR signaling has been found to reverse EMT and decrease the CSC phenotype in lung cancer cells, as mTOR is a downstream target of Akt [19]. The Akt/mTOR signaling pathway can activate c-Myc, which plays a critical role in promoting the self-renewal and survival of CSCs in various cancers, including lung cancer [63].…”

“…The activation of the Akt signaling pathway promotes the formation of tumor-initiating cells by inducing EMT and facilitating cancer cell migration and invasion [17]. The suppression of the mammalian target of rapamycin (mTOR), the downstream target of Akt signaling, has been found to reduce invasion and cell migration as well as block CSCs from forming in NSCLC [18,19]. Moreover, c-Myc is a downstream target of the Akt/mTOR pathway, and its expression has been linked to both the EMT process and stem cell-like properties in cancer [20].…”

20-Hydroxyecdysone Confers Antioxidant and Antineoplastic Properties in Human Non-Small Cell Lung Cancer Cells

“…All in all, we observed 619 down-regulated (Table S4) and 61 up-regulated (Table S5) genes. Among the 20E-down-regulated genes in lung cancer cells, several of them are considered to be oncogenes, including Notch3 ( [34]), HSF1 ( [35]), mTOR ( [36]), SOX12 ( [37]), KLF16 (Kruppel-like factor 16, [38]), and others (Table S4). It is also important to note that 20E suppressed genes which code for ABC-transporters, including those conferring multidrug resistance ABCB6 and ABCC1 (MRP1), a cytokine TGF-β, MAPK signaling components, subunits of all respiratory chain complexes, and a number of amino acid importers (Figure 4A,B, Table S4).…”

“…H460, A549, and H1299 cell lines are frequently used as widely accepted cell models in the context of the metabolic rewiring of NSCLC [41][42][43]. To study the impact of 20E on the expression of genes involved in glycolysis and one-carbon metabolism, H460, A549, and H1299 NSCLC cells were treated with the extended concentration range of 20E (0.01- Among the 20E-down-regulated genes in lung cancer cells, several of them are considered to be oncogenes, including Notch3 ( [34]), HSF1 ( [35]), mTOR ( [36]), SOX12 ( [37]), KLF16 (Kruppel-like factor 16, [38]), and others (Table S4). It is also important to note that 20E suppressed genes which code for ABC-transporters, including those conferring multidrug resistance ABCB6 and ABCC1 (MRP1), a cytokine TGF-β, MAPK signaling components, subunits of all respiratory chain complexes, and a number of amino acid importers (Figure 4A,B, Table S4).…”