Cancerous perturbations within the ERK, PI3K/Akt, and Wnt/β-catenin signaling network constitutively activate inter-pathway positive feedback loops

Padala, Rahul Rao; Karnawat, Rishabh; Viswanathan, Satish Bharathwaj; Thakkar, Abhishek Vijay; Das, Asim Bikas

doi:10.1039/c6mb00786d

Cited by 29 publications

(39 citation statements)

References 81 publications

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“…p-Akt regulates a variety of biological activities such as cell proliferation, apoptosis, differentiation, apoptosis, migration, glucose transport and release of inflammatory cytokines through activating downstream target proteins. As it is still difficult to directly detect the expression of PI3K, the level of PI3K is generally inferred through measuring the level of p-Akt by western blot because it is the only protein known to be affected by PI3K (20,21).…”

Section: Discussionmentioning

confidence: 99%

PTEN promotes apoptosis of H2O2‑injured rat nasal epithelial cells through PI3K/Akt and other pathways

2017

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Chronic rhinosinusitis (CRS) is a form of chronic inflammation of the nasal cavity and paranasal sinus with multi‑causal pathogenesis, including oxidative stress. Several lines of evidence have demonstrated that the phosphatase and tensin homolog gene (PTEN) can inhibit the activation of phosphoinositide 3‑kinase (PI3K) to affect phosphorylation of Akt. Importantly, the PI3K/PTEN/Akt signaling pathway is associated with various types of tumors, chronic inflammatory diseases, and autoimmune disease through its regulation of cell growth, apoptosis, proliferation, and metabolism. This in vitro study aimed to investigate the role of PTEN and the relationship between PTEN and the PI3K/Akt pathway in nasal epithelial cells under oxidative stress. H2O2 treatment was applied to induce a cell injury model of oxidative stress in rat nasal epithelial cells. Cells were divided into control, H2O2, H2O2+PTEN, and H2O2+siPTEN groups. Cell viability was measured using the CCK‑8 assay, and reactive oxygen species (ROS) levels and apoptosis rates were analyzed by flow cytometry (FCM). Oxidative parameters, including ROS, catalase (CAT), and malondialdehyde (MDA), were tested by enzyme‑linked immunosorbent assay (ELISA). The expression of apoptosis‑related genes and PI3K/Akt pathway was assayed by quantitative PCR (qPCR) and western blot. In H2O2‑injured cells, oxidative stress, due to increased ROS levels and apoptosis rates, was induced, and PTEN aggravated the injury. The levels of both p‑Akt and PTEN in H2O2‑injured cells were positively correlated and higher than in control cells. Unknown regulatory protein(s) may exist in the PI3K/PTEN/Akt pathway or the PTEN and PI3K/Akt pathways may be two independent signaling pathways that have cross interactions.

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Section: Discussionmentioning

confidence: 99%

PTEN promotes apoptosis of H2O2‑injured rat nasal epithelial cells through PI3K/Akt and other pathways

2017

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“…For instance, circRNAs appear to have a role in regulating the Wnt/β-catenin pathway (Huang et al, 2015). Wnt signaling has been shown to contribute to human tumor progression (Padala et al, 2017). If circRNAs are confirmed to regulate this pathway, circRNAs could also be targeted in order to interrupt this pathway and inhibit tumor growth and development.…”

Section: Circrnas and Cancermentioning

confidence: 99%

Circular RNAs: Biogenesis, Function and Role in Human Diseases

Greene

Baird

Brady

et al. 2017

Front. Mol. Biosci.

468

385

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Circular RNAs (circRNAs) are currently classed as non-coding RNA (ncRNA) that, unlike linear RNAs, form covalently closed continuous loops and act as gene regulators in mammals. They were originally thought to represent errors in splicing and considered to be of low abundance, however, there is now an increased appreciation of their important function in gene regulation. circRNAs are differentially generated by backsplicing of exons or from lariat introns. Unlike linear RNA, the 3′ and 5′ ends normally present in an RNA molecule have been joined together by covalent bonds leading to circularization. Interestingly, they have been found to be abundant, evolutionally conserved and relatively stable in the cytoplasm. These features confer numerous potential functions to circRNAs, such as acting as miRNA sponges, or binding to RNA-associated proteins to form RNA-protein complexes that regulate gene transcription. It has been proposed that circRNA regulate gene expression at the transcriptional or post-transcriptional level by interacting with miRNAs and that circRNAs may have a role in regulating miRNA function in cancer initiation and progression. circRNAs appear to be more often downregulated in tumor tissue compared to normal tissue and this may be due to (i) errors in the back-splice machinery in malignant tissues, (ii) degradation of circRNAs by deregulated miRNAs in tumor tissue, or (iii) increasing cell proliferation leading to a reduction of circRNAs. circRNAs have been identified in exosomes and more recently, chromosomal translocations in cancer have been shown to generate aberrant fusion-circRNAs associated with resistance to drug treatments. In addition, though originally thought to be non-coding, there is now increasing evidence to suggest that select circRNAs can be translated into functional proteins. Although much remains to be elucidated about circRNA biology and mechanisms of gene regulation, these ncRNAs are quickly emerging as potential disease biomarkers and therapeutic targets in cancer.

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“…Both pathways activate a cascade of downstream kinases which lead to the activation of specific transcription factors, including the cAMP response element binding protein (CREB), which is upregulated in GBM and has a role in NSPC and GBM cell proliferation 12,45 . Emerging evidence suggest that oncogenic PI3K and MAPK signals converge with Wnt signaling to regulate cancer cell growth and proliferation 44 and that in GBM, Wnt signaling has a role in cancer stem cell maintenance 48 .…”

Section: Introductionmentioning

confidence: 99%

PI3K activation in neural stem cells drives tumorigenesis which can be suppressed by targeting CREB

Daniel

Filiz

Brown

et al. 2017

Preprint

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2Hyperactivation of the PI3K signaling is common in human cancers, including gliomas, but the precise role of the pathway in glioma biology remains to be determined. Some limited understanding of PI3K signaling in brain cancer come from studies on neural stem/progenitor cells (NSPCs) where signals transmitted via the PI3K pathway cooperate with other intracellular pathways and downstream transcription factors to regulate NSPC proliferation. To investigate the role for the PI3K pathway in glioma initiation and development, we generated a mouse model targeting the inducible expression of a Pik3ca H1047A oncogenic mutation and simultaneous deletion of the PI3K negative regulator, Pten, in NSPCs. We show that the expression of a Pik3ca H1047A was sufficient to initiate tumorigenesis but that simultaneous loss of Pten, was required for the development of invasive, high-grade glioma. Mutant NSPCs exhibited enhanced neurosphere forming capacity which correlated with increased Wnt signaling. We also show that loss of CREB in Pik3ca-PTEN tumors led to a longer symptom-free survival in mice. Taken together, our findings present a novel mouse model for high-grade glioma with which we demonstrate that the PI3K pathway is important for initiation of tumorigenesis and that disruption of downstream CREB signaling attenuates tumor expansion.

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Cancerous perturbations within the ERK, PI3K/Akt, and Wnt/β-catenin signaling network constitutively activate inter-pathway positive feedback loops

Cited by 29 publications

References 81 publications

PTEN promotes apoptosis of H2O2‑injured rat nasal epithelial cells through PI3K/Akt and other pathways

PTEN promotes apoptosis of H2O2‑injured rat nasal epithelial cells through PI3K/Akt and other pathways

Circular RNAs: Biogenesis, Function and Role in Human Diseases

PI3K activation in neural stem cells drives tumorigenesis which can be suppressed by targeting CREB

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