Novel Dual PI3K/mTOR Inhibitor,Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells

Deregulated PI3K/AKT/mTOR signalling commonly exists in glioblastoma, making this axis an attractive target for therapeutic manipulation. Given that activation of PI3K/AKT/mTOR promotes tumour growth, metastasis, and resistance to anticancer therapies, mTOR inhibitors show promise in the treatment of cancer. The aim of this study was to investigate the underlying mechanism of novel dual PI3K/mTOR inhibitor, Apitolisib (GDC-0980), in A-172 and U-118-MG GBM tumour cell line suppression. It has been demonstrated that GDC-0980 induces time- and dose-dependent cytotoxicity and apoptosis in investigated glioma cell lines. In our study, the strongest induction of apoptosis was exhibited in the A-172 line after 48 h of incubation with 20 µM GDC-0980, where we observed 46.47% of apoptotic cells. In conclusion, we first discovered that dual PI3K/mTOR blockade by GDC-0980 markedly suppressed survival of human GBM cells and induced apoptosis, independent of the ER stress-mediated DR5 activation. We suggest that GDC-0980, by exerting an inhibitory effect on PERK expression, may thus block its inhibitory effect on protein synthesis, leading to intensification of translation, and this may result in an increase in apoptosis. On the other hand, CHOP stimulates protein synthesis and increases apoptosis. These findings suggest that GDC-0980 may be a candidate for further evaluation as a chemotherapeutic agent for anti-GBM therapy.     

Metformin Attenuates UVA-Induced Skin Photoaging by Suppressing Mitophagy and the PI3K/AKT/mTOR Pathway

Ultraviolet (UV) radiation is a major cause of photoaging that can induce DNA damage, oxidative stress, and cellular aging. Metformin (MF) can repair DNA damage, scavenge reactive oxygen species (ROS), and protect cells. However, the mechanism by which MF inhibits cell senescence in chronic skin damage induced by UVA is unclear. In this study, human foreskin fibroblasts (HFFs) treated with UVA were used as an in vitro model and UVA-induced skin photoaging in Kunming mice was used as an in vivo model to investigate the potential skin protective mechanism of MF. The results revealed that MF treatment attenuated UVA-induced cell viability, skin aging, and activation of the PI3K/AKT/mTOR signaling pathway. Furthermore, MF treatment alleviated the mitochondrial oxidative stress and decreased mitophagy. Knockdown of Parkin by siRNA increased the clearance of MF in senescent cells. The treatment of Kunming mice with MF at a dose of 10 mg/kg/day significantly reduced UVA-induced skin roughness, epidermal thinning, collagen degradation, and skin aging. In conclusion, our experimental results suggest that MF exerts anti-photoaging effects by inhibiting mitophagy and the PI3K/AKT/mTOR signaling pathway. Therefore, our study improves the current understanding of the protective mechanism of MF against photoaging.     

Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects

Although pancreatic cancer (PC) was considered in the past an orphan cancer type due to its low incidence, it may become in the future one of the leading causes of cancer death. Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of PC, being a highly aggressive malignancy and having a 5-year survival rate of less than 10%. Non-modifiable (family history, age, genetic susceptibility) and modifiable (smoking, alcohol, acute and chronic pancreatitis, diabetes mellitus, intestinal microbiota) risk factors are involved in PC pathogenesis. Chronic inflammation induced by various factors plays crucial roles in PC development from initiation to metastasis. In multiple malignant conditions such as PC, cytokines, chemokines, and growth factors activate the class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) signaling pathway, which plays key roles in cell growth, survival, proliferation, metabolism, and motility. Currently, mTOR, AKT, and PI3K inhibitors are used in clinical studies. Moreover, PI3K/mTOR dual inhibitors are being tested in vitro and in vivo with promising results for PC patients. The main aim of this review is to present PC incidence, risk factors, tumor microenvironment development, and PI3K/AKT/mTOR dysregulation and inhibitors used in clinical, in vivo, and in vitro studies.     

PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects

Breast cancer is a serious health problem worldwide, representing the second cause of death through malignancies among women in developed countries. Population, endogenous and exogenous hormones, and physiological, genetic and breast-related factors are involved in breast cancer pathogenesis. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is a signaling pathway involved in cell proliferation, survival, invasion, migration, apoptosis, glucose metabolism and DNA repair. In breast tumors, PIK3CA somatic mutations have been reported, located in exon 9 and exon 20. Up to 40% of PIK3CA mutations are estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) -negative in primary and metastatic breast cancer. HER2 is overexpressed in 20–30% of breast cancers. HER1, HER2, HER3 and HER4 are membrane receptor tyrosine kinases involved in HER signaling to which various ligands can be attached, leading to PI3K/AKT activation. Currently, clinical studies evaluate inhibitors of the PI3K/AKT/mTOR axis. The main purpose of this review is to present general aspects of breast cancer, the components of the AKT signaling pathway, the factors that activate this protein kinase B, PI3K/AKT-breast cancer mutations, PI3K/AKT/mTOR-inhibitors, and the relationship between everolimus, temsirolimus and endocrine therapy.     

Silencing DTX3L Inhibits the Progression of Cervical Carcinoma by Regulating PI3K/AKT/mTOR Signaling Pathway

Cervical carcinoma (CC) is the second most prevalent gynecologic cancer in females across the world. To obtain a better understanding of the mechanisms underlying the development of CC, high-resolution label-free mass spectrometry was performed on CC and adjacent normal tissues from eight patients. A total of 2631 proteins were identified, and 46 significant differently expressed proteins (DEPs) were found between CC and normal tissues (p < 0.01, fold change >10 or <0.1). Ingenuity pathway analysis revealed that the majority of the proteins were involved in the regulation of eIF4 and p70S6K signaling and mTOR signaling. Among 46 DEPs, Integrinβ6 (ITGB6), PPP1CB, TMPO, PTGES3 (P23) and DTX3L were significantly upregulated, while Desmin (DES) was significantly downregulated in CC tissues compared with the adjacent normal tissues. In in vivo and in vitro experiments, DTX3L knockdown suppressed CC cell proliferation, migration, invasion and xenograft tumorigenesis, and enhanced cell apoptosis. Combination of silencing DTX3L and cisplatin treatment induced higher apoptosis percentage compared to cisplatin treatment alone. Moreover, DTX3L silencing inhibited the PI3K/AKT/mTOR signal pathway. Thus, our results suggested DTX3L could regulate CC progression through the PI3K/AKT/mTOR signal pathway and is potentially a novel biomarker and therapeutic target for CC.     

The Role of mTOR Signaling as a Therapeutic Target in Cancer

The aim of this review was to summarize current available information about the role of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in cancer as a potential target for new therapy options. The mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) signaling are critical for the regulation of many fundamental cell processes including protein synthesis, cell growth, metabolism, survival, catabolism, and autophagy, and deregulated mTOR signaling is implicated in cancer, metabolic dysregulation, and the aging process. In this review, we summarize the information about the structure and function of the mTOR pathway and discuss the mechanisms of its deregulation in human cancers including genetic alterations of PI3K/AKT/mTOR pathway components. We also present recent data regarding the PI3K/AKT/mTOR inhibitors in clinical studies and the treatment of cancer, as well the attendant problems of resistance and adverse effects.     

Aromadendrin Protects Neuronal Cells from Methamphetamine-Induced Neurotoxicity by Regulating Endoplasmic Reticulum Stress and PI3K/Akt/mTOR Signaling Pathway

Methamphetamine (METH) is a highly addictive drug that induces irreversible damage to neuronal cells and pathological malfunction in the brain. Aromadendrin, isolated from the flowers of Chionanthus retusus, has been shown to have anti-inflammatory or anti-tumor activity. Nevertheless, it has been reported that METH exacerbates neurotoxicity by inducing endoplasmic reticulum (ER) stress via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in neuronal cells. There is little evidence that aromadendrin protects cells from neurotoxicity induced by METH. In this study, we found that aromadendrin partially suppressed the METH-induced cell death in SH-SY5y cells without causing cytotoxicity. Aromadendrin regulated METH-induced ER stress by preserving the phosphorylation of the PI3K/Akt/mTOR signaling pathway in METH-exposed SH-SY5y cells. In addition, aromadendrin mitigated METH-induced autophagic and the apoptotic pathways in METH-exposed SH-SY5y cells. Mechanistic studies revealed that pre-treatment with aromadendrin restored the expression of anti-apoptotic proteins in METH-exposed conditions. The inhibitor assay confirmed that aromadendrin-mediated restoration of mTOR phosphorylation protected cells from autophagy and apoptosis in METH-exposed cells. Therefore, these findings suggest that aromadendrin relatively has a protective effect on SH-SY5y cells against autophagy and apoptosis induced by METH via regulation of ER stress and the PI3K/Akt/mTOR signaling pathway.     

The mTOR Signalling Pathway in Human Cancer

The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.     

PI3K/PTEN/AKT Signaling Pathways in Germ Cell Development and Their Involvement in Germ Cell Tumors and Ovarian Dysfunctions

Several studies indicate that the PI3K/PTEN/AKT signaling pathways are critical regulators of ovarian function including the formation of the germ cell precursors, termed primordial germ cells, and the follicular pool maintenance. This article reviews the current state of knowledge of the functional role of the PI3K/PTEN/AKT pathways during primordial germ cell development and the dynamics of the ovarian primordial follicle reserve and how dysregulation of these signaling pathways may contribute to the development of some types of germ cell tumors and ovarian dysfunctions.     

Blocking Autophagic Flux Enhances Matrine-Induced Apoptosis in Human Hepatoma Cells

Autophagy, a self-defense mechanism, has been found to be associated with drug resistance in hepatocellular carcinoma (HCC). Our study was designed to investigate the role and related mechanisms of autophagy in matrine-induced apoptosis in hepatoma cells of HepG2 and Bel₇₄₀₂. Cell apoptosis was detected by flow cytometry analysis (Annexin V–FITC/PI double-staining assay), the activity and activating cleavages of caspase-3, -8, and -9. MTT assay and colony forming assay were used to assess the effect of matrine on growth and proliferation of HCC cells. Autophagic flux in HCC cells was analyzed using the expression of LC3BI/II and p62/SQSTM1, GFP-LC3 transfection, and transmission electron microscopy. Moreover, regarding to the associated mechanisms, the effects of matrine on the phosphoinositide 3-kinase/AKT/mTOR pathway and beclin-1 were studied. Our results showed that: (1) both autophagy and apoptosis could be induced by treatment with matrine; (2) using the autophagic inhibitor chloroquine and beclin-1 small-interfering RNA, cell apoptosis induced by matrine could be enhanced in a caspase-dependent manner; and (3) autophagy was induced via inhibition of PI3K/AKT/mTOR pathway and up-regulation of beclin-1. In conclusion, inhibition of autophagy could enhance matrine-induced apoptosis in human hepatoma cells.     

Targeting AKT in ER-Positive HER2-Negative Metastatic Breast Cancer: From Molecular Promises to Real Life Pitfalls?

The AKT protein kinase plays a central role in several interconnected molecular pathways involved in growth, apoptosis, angiogenesis, and cell metabolism. It thereby represents a therapeutic target, especially in hormone receptor-positive (HR) breast cancers, where the PI3K/AKT signaling pathway is largely hyperactivated. Moreover, resistance to therapeutic classes, including endocrine therapy, is associated with the constitutive activation of the PI3K/AKT pathway. Improved knowledge on the molecular mechanisms underlying resistance to endocrine therapy has led to the diversification of the therapeutic arsenal, notably with the development of PI3K and mTOR inhibitors, which are currently approved for the treatment of advanced HR-positive breast cancer patients. AKT itself constitutes a novel pharmacological target for which AKT inhibitors have been developed and tested in clinical trials. However, despite its pivotal role in cell survival and anti-apoptotic mechanisms, as well as in endocrine therapy resistance, few drugs have been developed and are available for clinical practice. The scope of the present review is to focus on the pivotal role of AKT in metastatic breast cancer through the analysis of its molecular features and to discuss clinical implications and remaining challenges in the treatment of HR-positive metastatic breast cancer.     

Immunomodulatory Properties of PI3K/AKT/mTOR and MAPK/MEK/ERK Inhibition Augment Response to Immune Checkpoint Blockade in Melanoma and Triple-Negative Breast Cancer

Hyperactivation of PI3K/AKT/mTOR and MAPK/MEK/ERK signaling pathways is commonly observed in many cancers, including triple-negative breast cancer (TNBC) and melanoma. Moreover, the compensatory upregulation of the MAPK/MEK/ERK pathway has been associated with therapeutic resistance to targeted inhibition of the PI3K/AKT/mTOR pathway, and vice versa. The immune-modulatory effects of both PI3K and MAPK inhibition suggest that inhibition of these pathways might enhance response to immune checkpoint inhibitors (ICIs). ICIs have become the standard-of-care for metastatic melanoma and are recently an option for TNBC when combined with chemotherapy, but alternative options are needed when resistance develops. In this review, we present the current mechanistic understandings, along with preclinical and clinical evidence, that outline the efficacy and safety profile of combinatorial or sequential treatments with PI3K inhibitors, MAPK inhibitors, and ICIs for treatment of malignant melanoma and metastatic TNBC. This approach may present a potential strategy to overcome resistance in patients who are a candidate for ICI therapy with tumors harboring either or both of these pathway-associated mutations.     

Involvement of PI3K Pathway in Glioma Cell Resistance to Temozolomide Treatment

The aim of the study was to investigate the anticancer potential of LY294002 (PI3K inhibitor) and temozolomide using glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cells. Apoptosis, autophagy, necrosis, and granules in the cytoplasm were identified microscopically (fluorescence and electron microscopes). The mitochondrial membrane potential was studied by flow cytometry. The activity of caspases 3, 8, and 9 and Akt was evaluated fluorometrically, while the expression of Beclin 1, PI3K, Akt, mTOR, caspase 12, and Hsp27 was determined by immunoblotting. SiRNA was used to block Hsp27 and PI3K expression. Cell migration and localization of Hsp27 were tested with the wound healing assay and immunocytochemistry, respectively. LY294002 effectively diminished the migratory potential and increased programmed death of T98G and MOGGCCM. Autophagy was dominant in MOGGCCM, while apoptosis was dominant in T98G. LY294002 with temozolomide did not potentiate cell death but redirected autophagy toward apoptosis, which was correlated with ER stress. A similar effect was observed after blocking PI3K expression with siRNA. Transfection with Hsp27 siRNA significantly increased apoptosis related to ER stress. Our results indicate that inhibition of the PI3K/Akt/mTOR pathway sensitizes glioma cells to apoptosis upon temozolomide treatment, which was correlated with ER stress. Hsp27 increases the resistance of glioma cells to cell death upon temozolomide treatment.     

PRKAR1B-AS2 Long Noncoding RNA Promotes Tumorigenesis,Survival, and Chemoresistance via the PI3K/AKT/mTOR Pathway

Many long noncoding RNAs have been implicated in tumorigenesis and chemoresistance; however, the underlying mechanisms are not well understood. We investigated the role of PRKAR1B-AS2 long noncoding RNA in ovarian cancer (OC) and chemoresistance and identified potential downstream molecular circuitry underlying its action. Analysis of The Cancer Genome Atlas OC dataset, in vitro experiments, proteomic analysis, and a xenograft OC mouse model were implemented. Our findings indicated that overexpression of PRKAR1B-AS2 is negatively correlated with overall survival in OC patients. Furthermore, PRKAR1B-AS2 knockdown-attenuated proliferation, migration, and invasion of OC cells and ameliorated cisplatin and alpelisib resistance in vitro. In proteomic analysis, silencing PRKAR1B-AS2 markedly inhibited protein expression of PI3K-110α and abrogated the phosphorylation of PDK1, AKT, and mTOR, with no significant effect on PTEN. The RNA immunoprecipitation detected a physical interaction between PRKAR1B-AS2 and PI3K-110α. Moreover, PRKAR1B-AS2 knockdown by systemic administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with PRKAR1B-AS2–specific small interfering RNA enhanced cisplatin sensitivity in a xenograft OC mouse model. In conclusion, PRKAR1B-AS2 promotes tumor growth and confers chemoresistance by modulating the PI3K/AKT/mTOR pathway. Thus, targeting PRKAR1B-AS2 may represent a novel therapeutic approach for the treatment of OC patients.     

BMP4 Protects Rat Pulmonary Arterial Smooth Muscle Cells from Apoptosis by PI3K/AKT/Smad1/5/8 Signaling

Bone morphogenetic protein-4 (BMP4), a member of the transforming growth factor β (TGF-β) family of growth factors, is activated and increased under hypoxic conditions, which plays an important role in the progression of pulmonary arterial hypertension (PAH). Previous studies have shown that BMP4 is involved in the regulation of proliferation, differentiation, migration and apoptosis of various cell types. However, the precise mechanisms involved in the regulation of pulmonary artery smooth muscle cells (PASMCs) in PAH are still incompletely understood. It has been reported that AKT is a critical regulator of cell survival and vascular remodeling. Therefore, there may be crosstalk between BMP4 anti-apoptotic processes and PI3K/AKT survival effect in rat PASMCs. To test this hypothesis, we performed confocal, cell viability measurement, mitochondrial potential, real-time polymerase chain reaction (PCR), and Western blot analysis to determine the role of BMP4 on cell survival and apoptosis. We found that hypoxia up-regulated the expression of BMP4. BMP4 promoted cell survival, reduced mitochondrial depolarization, and increased the expression of Bcl-2 and procaspase-3 in PASMCs under serum-deprived condition. These effects were reversed by PI3K/AKT inhibitors ({"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 and wortmannin). Thus, these findings indicate that BMP4 protects PASMCs from apoptosis at least in part, mediated via the PI3K/AKT pathway.     

Dapagliflozin Mitigates Doxorubicin-Caused Myocardium Damage by Regulating AKT-Mediated Oxidative Stress,Cardiac Remodeling,and Inflammation

Doxorubicin (Dox) is a commonly used anthracycline chemotherapy with a side effect of cardiotoxicity, which may increase the risk of heart failure for cancer patients. Although various studies have demonstrated the cardioprotective property of dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, the detailed mechanism underlying its effect on Dox-induced cardiomyopathy is still limited. In this study, we showed that DAPA induced the activation of AKT/PI3K signaling in cardiac myoblast H9c2 cells following Dox treatment, leading to the upregulation of antioxidant HO-1, NQO1, and SOD, as well as an improved mitochondrial dysfunction via Nrf2. In addition, the reduced oxidative stress resulted in the downregulation of hypertrophy (ANP and BNP) and fibrosis (phospho-Smad3, collagen I, fibronectin, and α-SMA) markers. Furthermore, the inflammatory IL-8 concentration was inhibited after DAPA, possibly through PI3K/AKT/Nrf2/p38/NF-κB signaling. Moreover, our results were validated in vivo, and echocardiography results suggested an improved cardiac function in DAPA-receiving rats. In summary, we demonstrated that the administration of DAPA could mitigate the Dox-elicited cardiotoxicity by reducing oxidative stress, mitochondrial dysfunction, fibrosis, hypertrophy, and inflammation via PI3K/AKT/Nrf2 signaling.     

Cardiac Protective Effect of Kirenol against Doxorubicin-Induced Cardiac Hypertrophy in H9c2 Cells through Nrf2 Signaling via PI3K/AKT Pathways

Kirenol (KRL) is a biologically active substance extracted from Herba Siegesbeckiae. This natural type of diterpenoid has been widely adopted for its important anti-inflammatory and anti-rheumatic properties. Despite several studies claiming the benefits of KRL, its cardiac effects have not yet been clarified. Cardiotoxicity remains a key concern associated with the long-term administration of doxorubicin (DOX). The generation of reactive oxygen species (ROS) causes oxidative stress, significantly contributing to DOX-induced cardiac damage. The purpose of the current study is to investigate the cardio-protective effects of KRL against apoptosis in H9c2 cells induced by DOX. The analysis of cellular apoptosis was performed using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining assay and measuring the modulation in the expression levels of proteins involved in apoptosis and Nrf2 signaling, the oxidative stress markers. Furthermore, Western blotting was used to determine cell survival. KRL treatment, with Nrf2 upregulation and activation, accompanied by activation of PI3K/AKT, could prevent the administration of DOX to induce cardiac oxidative stress, remodeling, and other effects. Additionally, the diterpenoid enhanced the activation of Bcl2 and Bcl-xL, while suppressing apoptosis marker proteins. As a result, KRL is considered a potential agent against hypertrophy resulting from cardiac deterioration. The study results show that KRL not only activates the IGF-IR-dependent p-PI3K/p-AKT and Nrf2 signaling pathway, but also suppresses caspase-dependent apoptosis.     

Cell Death Conversion under Hypoxic Condition in Tumor Development and Therapy

Hypoxia, which is common during tumor progression, plays important roles in tumor biology. Failure in cell death in response to hypoxia contributes to progression and metastasis of tumors. On the one hand, the metabolic and oxidative stress following hypoxia could lead to cell death by triggering signal cascades, like LKB1/AMPK, PI3K/AKT/mTOR, and altering the levels of effective components, such as the Bcl-2 family, Atg and p62. On the other hand, hypoxia-induced autophagy can serve as a mechanism to turn over nutrients, so as to mitigate the adverse condition and then avoid cell death potentially. Due to the effective role of hypoxia, this review focuses on the crosstalk in cell death under hypoxia in tumor progression. Additionally, the illumination of cell death in hypoxia could shed light on the clinical applications of cell death targeted therapy.     

Crosstalk between MicroRNA and Oxidative Stress in Primary Open-Angle Glaucoma

Reactive oxygen species (ROS) plays a key role in the pathogenesis of primary open-angle glaucoma (POAG), a chronic neurodegenerative disease that damages the trabecular meshwork (TM) cells, inducing apoptosis of the retinal ganglion cells (RGC), deteriorating the optic nerve head, and leading to blindness. Aqueous humor (AH) outflow resistance and intraocular pressure (IOP) elevation contribute to disease progression. Nevertheless, despite the existence of pharmacological and surgical treatments, there is room for the development of additional treatment approaches. The following review is aimed at investigating the role of different microRNAs (miRNAs) in the expression of genes and proteins involved in the regulation of inflammatory and degenerative processes, focusing on the delicate balance of synthesis and deposition of extracellular matrix (ECM) regulated by chronic oxidative stress in POAG related tissues. The neutralizing activity of a couple of miRNAs was described, suggesting effective downregulation of pro-inflammatory and pro-fibrotic signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), transforming growth factor-beta 2 (TGF-β2), Wnt/β-Catenin, and PI3K/AKT. In addition, with regards to the elevated IOP in many POAG patients due to increased outflow resistance, Collagen type I degradation was stimulated by some miRNAs and prevented ECM deposition in TM cells. Mitochondrial dysfunction as a consequence of oxidative stress was suppressed following exposure to different miRNAs. In contrast, increased oxidative damage by inhibiting the mTOR signaling pathway was described as part of the action of selected miRNAs. Summarizing, specific miRNAs may be promising therapeutic targets for lowering or preventing oxidative stress injury in POAG patients.