Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial-mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.

/pdf/role-of-pi3k-akt-pathway-in-cancer-the-framework-of-3f2u6pm7nk.pdf

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior.

Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma of the head and neck region which mainly distributes in southern China and Southeast Asia and has a crucial association with the Epstein–Barr virus. Based on epidemiological data, both incidence and mortality of NPC have significantly declined in recent decades grounded on the improvement of living standard and medical level in an endemic region, in particular, with the clinical use of individualized chemotherapy and intensity-modulated radiotherapy (IMRT) which profoundly contributes to the cure rate of NPC patients. To tackle the challenges including local recurrence and distant metastasis in the current NPC treatment, we discussed the implication of using targeted therapy against critical molecules in various signal pathways, and how they synergize with chemoradiotherapy in the NPC treatment. Combination treatment including targeted therapy and IMRT or concurrent chemoradiotherapy is presumably to be future options, which may reduce radiation or chemotherapy toxicities and open new avenues for the improvement of the expected functional outcome for patients with advanced NPC.

/pdf/advances-in-targeted-therapy-mainly-based-on-signal-pathways-34hcvrm3yw.pdf

Advances in targeted therapy mainly based on signal pathways for nasopharyngeal carcinoma.

Lymph node metastasis is the main cause of poor prognosis of head and neck squamous carcinoma (HNSCC) patients. N6-methyladenosine (m6A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression, and as a novel m6A reader protein, IGF2BP2 has been implicated in tumor progression and metastasis. However, not much is currently known about the functional roles of IGF2BP2 in HNSCC, and whether IGF2BP2 regulates lymphatic metastasis through m6A modification in HNSCC remains to be determined.The expression and overall survival (OS) probability of m6A-related regulators in HNSCC were analyzed with The Cancer Genome Atlas (TCGA) dataset and GEPIA website tool, respectively. The expression levels of IGF2BP2 were measured in HNSCC tissues and normal adjacent tissues. To study the effects of IGF2BP2 on HNSCC cell metastasis in vitro and in vivo, gain- and loss- of function methods were employed. RIP, MeRIP, luciferase reporter and mRNA stability assays were performed to explore the epigenetic mechanism of IGF2BP2 in HNSCC.We investigated 20 m6A-related regulators in HNSCC and discovered that only the overexpression of IGF2BP2 was associated with a poor OS probability and an independent prognostic factor for HNSCC patients. Additionally, we demonstrated that IGF2BP2 was overexpressed in HNSCC tissues, and significantly correlated to lymphatic metastasis and poor prognosis. Functional studies have shown that IGF2BP2 promotes both HNSCC cell migration as well as invasion via the epithelial-mesenchymal transition (EMT) process in vitro, and IGF2BP2 knockdown significantly inhibited lymphatic metastasis and lymphangiogenesis in vivo. Mechanistic investigations revealed that Slug, a key EMT-related transcriptional factor, is the direct target of IGF2BP2, and essential for IGF2BP2-regulated EMT and metastasis in HNSCC. Furthermore, we demonstrated that IGF2BP2 recognizes and binds the m6A site in the coding sequence (CDS) region of Slug and promotes its mRNA stability.Collectively, our study uncovers the oncogenic role and potential mechanism of IGF2BP2, which serves as a m6A reader, in controlling lymphatic metastasis and EMT in HNSCC, suggesting that IGF2BP2 may act as a therapeutic target and prognostic biomarker for HNSCC patients with metastasis. 

/pdf/rna-n6-methyladenosine-reader-igf2bp2-promotes-lymphatic-2e9uuu9s.pdf

RNA N6-methyladenosine reader IGF2BP2 promotes lymphatic metastasis and epithelial-mesenchymal transition of head and neck squamous carcinoma cells via stabilizing slug mRNA in an m6A-dependent manner

The reversible oxidation-reduction homeostasis mechanism functions as a specific signal transduction system, eliciting related physiological responses. Disruptions to redox homeostasis can have negative consequences, including the potential for cancer development and progression, which are closely linked to a series of redox processes, such as adjustment of reactive oxygen species (ROS) levels and species, changes in antioxidant capacity, and differential effects of ROS on downstream cell fate and immune capacity. The tumor microenvironment (TME) exhibits a complex interplay between immunity and regulatory cell death, especially autophagy and apoptosis, which is crucially regulated by ROS. The present study aims to investigate the mechanism by which multi-source ROS affects apoptosis, autophagy, and the anti-tumor immune response in the TME and the mutual crosstalk between these three processes. Given the intricate role of ROS in controlling cell fate and immunity, we will further examine the relationship between traditional cancer therapy and ROS. It is worth noting that we will discuss some potential ROS-related treatment options for further future studies. 

Multifaceted role of redox pattern in the tumor immune microenvironment regarding autophagy and apoptosis

Exosomal circRNAs in cancer: Implications for therapy resistance and biomarkers.

Exosomes, which are small extracellular vesicles, have been unveiled to carry circular RNAs (circRNAs). CircRNA paired-related homeobox 1 (circPRRX1) can be transferred by exosomes derived from gastric cancer cells. Here, we investigated the activity and mechanism of exosomal circPRRX1 in gastric tumorigenesis and radiation sensitivity. CircPRRX1, microRNA (miR)-596, and NF-κB activating protein (NKAP) were quantified by quantitative real-time PCR and immunoblotting. Cell proliferation, motility, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and transwell assays, respectively. Cell colony formation and survival were assessed by colony formation assays. Dual-luciferase reporter assays were performed to verify the direct relationship between miR-596 and circPRRX1 or NKAP. In-vivo xenograft studies were used to evaluate the role of exosomal circPRRX1 in tumor growth. Our data showed that circPRRX1 expression was elevated in human gastric cancer, and circPRRX1 could be transferred by exosomes from gastric cancer cells. Exosomal circPRRX1 affected cell proliferation, motility, invasion, and radiation sensitivity in vitro and tumor growth in vivo. Mechanistically, circPRRX1 directly regulated miR-596 expression, and exosomal circPRRX1 affected cell biological functions at least in part through miR-596. NKAP was identified as a direct target and functionally downstream effector of miR-596. Exosomal circPRRX1 modulated NKAP expression by acting as a competing endogenous RNA (ceRNA) for miR-596. Our findings suggest a new mechanism, the exosomal circPRRX1/miR-596/NKAP ceRNA crosstalk, in regulating gastric tumorigenesis and radiation sensitivity.

Exosomal circPRRX1 functions as a ceRNA for miR-596 to promote the proliferation, migration, invasion, and reduce radiation sensitivity of gastric cancer cells via the upregulation of NF-κB activating protein

Lung cancer, a most common clinically diagnosed malignancy grows rapidly and undergoes metastasis/diffusion to distant organs at a fast rate. In the present study gravacridondiol tetrazole (tetrazole) was synthesized and investigated for lung cancer growth inhibition potential in vitro. MTT assay and flow cytometry using propidium iodide were used to determine viability changes and DNA content distribution. Protein expression and apoptotic changes were detected by western blotting and Annexin-V/PI assays. Treatment with 12 μM tetrazole suppressed viabilities to 23% and 20% in A549 and NCI-H1819 cells, respectively. In tetrazole exposed cells, G1-phase cell count increased significantly compared to the control. Tetrazole-treatment of A549 and NCI-H1819 cells caused a prominent raise in LC3‑II and p-ERK1/2 expression at 72 h. The SQSTM1/p62 level, p-mTOR and p-p70S6K expression was lowered significantly in A549 and NCI-H1819 cells on exposure to tetrazole. Exposure to U1026 alleviated tetrazole mediated LC3II/I ratio increase in A549 and NCI-H1819 cells significantly (P<0.02) compared to tetrazole treated cells. Treatment with tetrazole and 3‑MA in combination led a significant (P<0.02) elevation in A549 and NCI-H1819 cell apoptotic count relative to tetrazole (12 μM) alone treated cells. Moreover, tetrazole and 3‑MA combination increased cleavage of caspase‑3 to a greater extent compared to tetrazole. In summary, tetrazole manifested anti-proliferative effect on lung cancer cells via autophagy over-activation and arrest of cell cycle. It deactivated ERK1/2 signalling and promoted mTOR signaling in A549 and NCI-H1819 cells to regulate cancer proliferation. Thus, tetrazole needs to be studied further as an anti-proliferative agent for treatment of lung cancer.

/pdf/lung-cancer-growth-inhibition-and-autophagy-activation-by-2hwzcwyz.pdf

Lung cancer growth inhibition and autophagy activation by tetrazole via ERK1/2 up-regulation and mTOR/p70S6K signaling down-regulation.

: of on the of To investigate the effect of shikonin on the oxidative damage of lung cancer cells and promotes cell senescence through p53/p21Waf signaling pathway. The lung adenocarcinoma A549 cells were cultured and made into cell suspension. The lung adenocarcinoma A549 cells were cultured for 12 h, 24 h and 48 h respectively with different concentrations of shikonin (0 μm, 2 μm and 4 μm) and the activity of lung adenocarcinoma A549 cells was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide method. The cell cycle of each group was measured by flow cytometry after 48 h of action of shikonin. The aging of each group of cells was determined by beta-galactosidase staining after 48 h of action of shikonin. The reactive oxygen species content in each group was determined by flow cytometry 48 h after the action of shikonin. The expression levels of cyclin D1, demethylase KDM2B, deoxyribonucleic acid damage marker protein p-H2AX, p53 and p21WAF were measured by Western blot. With the increase of shikonin concentration, the cell activity and the expression levels of cyclin D1 and KDM2B were significantly decreased, the proportion of resting phase/intermediate phase cells and senescent cells were significantly increased, the level of reactive oxygen species and the expression levels of p-H2AX, p53 and p21WAF were significantly increased (p<0.05). Shikonin can inhibit cell activity, induce oxidative damage and promote cell senescence, which may be achieved by activating p53/p21WAF signaling pathway.

/pdf/shikonin-induces-oxidative-damage-and-promotes-cell-3hx5xk4l.pdf

Shikonin Induces Oxidative Damage and Promotes Cell Senescence in Lung Cancer Cells through p53/p21WAF Signaling Pathway

Purpose Ionizing radiation (IR) is widely used for treating nasopharyngeal carcinoma (NPC). However, recent studies indicate that IR can also promote the migration and invasion of malignant tumors. Phosphatase 1 nuclear-targeting subunit (PNUTS), a novel interacting protein, was recently demonstrated to be involved in tumorigenesis and metastasis formation. This protein was hypothesized to take part in IR-induced migration and invasion in NPC cells in this study. Materials and methods Western blotting was used to detect how PNUTS was expressed in NPC cells with or without IR treatment. Wound-healing and Transwell assays were used to measure cell migration and invasion. Quantitative real-time PCR and Western blotting were used to determine the expression levels of PNUTS and epithelial-mesenchymal transition (EMT) proteins, respectively, after CNE-2 cells were infected with an adenovirus vector, ad-PNUTS, or transfected with PNUTS-specific siRNA. Finally, the expression levels of PI3K/AKT signaling-related proteins were detected by Western blotting. Results IR significantly promoted PNUTS expression and the migration and invasion in CNE-2 cells. Moreover, after exposure to IR, expression of the mesenchymal markers N-cadherin and vimentin increased, while that of the epithelial marker E-cadherin decreased. Silencing PNUTS remarkably attenuated IR-induced increases in cell migration and invasion and reversed the EMT process. Additionally, the overexpression of PNUTS restored the mobility and invasiveness of CNE-2 cells, which regained EMT characteristics. Furthermore, we found that PNUTS regulated IR-induced EMT via the PI3K/AKT signaling pathway. Conclusion Our research illustrates a relationship between PNUTS and IR-induced cell migration and invasion and provides a novel therapeutic target for preventing radiotherapy-induced metastasis in NPC patients.

/pdf/pnuts-mediates-ionizing-radiation-induced-cne-2-309emfv10g.pdf

PNUTS mediates ionizing radiation-induced CNE-2 nasopharyngeal carcinoma cell migration, invasion, and epithelial-mesenchymal transition via the PI3K/AKT signaling pathway.

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Exosomal circPRRX1 functions as a ceRNA for miR-596 to promote the proliferation, migration, invasion, and reduce radiation sensitivity of gastric cancer cells via the upregulation of NF-κB activating protein

Lung cancer growth inhibition and autophagy activation by tetrazole via ERK1/2 up-regulation and mTOR/p70S6K signaling down-regulation.

Shikonin Induces Oxidative Damage and Promotes Cell Senescence in Lung Cancer Cells through p53/p21WAF Signaling Pathway

PNUTS mediates ionizing radiation-induced CNE-2 nasopharyngeal carcinoma cell migration, invasion, and epithelial-mesenchymal transition via the PI3K/AKT signaling pathway.