Class I phosphoinositide 3-kinase (PI3K) regulatory subunits and their roles in signaling and disease

Rathinaswamy, Manoj Kumar; Burke, John E.

doi:10.1016/j.jbior.2019.100657

Cited by 73 publications

(62 citation statements)

References 88 publications

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“…The PI3K family, belong to kinases of inositol and phosphatidylinositol, were oncogenes according pervious report [23]. The regulatory subunit (p85a), the composition of PI3K, was encoded by PIK3R1 [24], while PI3K signaling was involved in multiple human diseases, including, inflammation, malignant tumor, and diabetes [25,26]. We supposed that PIK3R1 was an oncogene in malignant tumors.…”

Section: Discussionmentioning

confidence: 99%

CircHIPK3/miR-876-5p/PIK3R1 axis regulates regulation proliferation, migration, invasion, and glutaminolysis in gastric cancer cells

Tian

Liang

et al. 2020

Cancer Cell Int

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Background: Circular RNAs (circRNAs) are a new group of non-coding RNAs that play vital roles in cancer occurrence, including gastric cancer (GC). Nevertheless, the role and underlying regulatory mechanisms of circHIPK3 in GC remain unclear. Methods: The expression levels of circHIPK3, miR-876-5p, and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) were estimated by real-time quantitative polymerase chain reaction (RT-qPCR) assay. The proliferation, migration, and invasion of GC cells were determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide (MTT) and transwell assay. Glutaminolysis of GC cells was assessed by measuring glutamine, glutamate, and α-ketoglutarate levels. The western blot was employed to examine the related-protein expression. The association between miR-876-5p and circHIPK3 or PIK3R1 was predicted and affirmed by bioinformatics database starBase v2.0 and dual-luciferase reporter assay, respectively. Eventually, the xenograft experiment was used to assess the role of circHIPK3 silencing in vivo. Results: CircHIPK3 was upregulated in GC tissues and cells compared with controls, and circHIPK3 was more resistance to RNase R than linear homeodomain interacting protein kinase 3 (HIPK3) mRNA. Silencing of circHIPK3 inhibited GC cells proliferation, migration, invasion, and glutaminolysis as well as tumor tumorigenic ability. Moreover, we also found that miR-876-5p, interacted with PIK3R1, was a target gene of circHIPK3. CircHIPK3 silencing induced effects on GC cells were abolished by silencing of miR-876-5p. In addition, upregulation of PIK3R1 inversed miR-876-5p overexpression-induced effects on GC cells. Conclusion: The circHIPK3 mediated the proliferation, migration, invasion, and glutaminolysis of GC cells partly through regulation of miR-876-5p/PIK3R1 axis by the mechanism of competing endogenous RNAs (ceRNA), indicating circHIPK3 was a GC-associated circRNA that promoted GC development.

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Section: Discussionmentioning

confidence: 99%

CircHIPK3/miR-876-5p/PIK3R1 axis regulates regulation proliferation, migration, invasion, and glutaminolysis in gastric cancer cells

Tian

Liang

et al. 2020

Cancer Cell Int

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“…Binding of insulin or insulin-like growth factor (IGF) to their receptor lead to recruitment and phosphorylation of the insulin receptor substrate and subsequent recruitment of PI3K. PI3K phosphorylates the inositol ring of the membrane phospholipid, phosphatidylinositol-4,5-biphosphate (PI-4,5-P 2 ) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP 3 ) at the cytoplasmic side of the cellular membrane (43). PIP 3 recruits a subset of pleckstrin homology (PH) domaincontaining proteins, such as the same protein kinase Akt and constitutively active phosphoinositide-dependent kinase 1 (PDK1) (44,45).…”

Section: Regulation Of Mtorc1 Signaling In Cancermentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients. de la Cruz López et al. mTORC1 and Mitochondrial Functions Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation, though no other collaboration, with with several of the authors AG and KC.

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“…PIK3R1 encodes the PI3K regulatory subunit p85α, while PIK3R2 and PIK3R3 encode p85β and p55γ respectively. [ 64 ] P85 subunits regulate PI3K activation by modulating the stability, conformation, and localization of the catalytic subunit. [ 65 ] P85α acts as a tumor suppressor, which strongly binding to the p110 catalytic subunit and increases its stability and inhibits its catalytic activity.…”

Section: Discussionmentioning

confidence: 99%

Investigating potential molecular mechanisms of serum exosomal miRNAs in colorectal cancer based on bioinformatics analysis

Wang¹,

Chen

Bao³

et al. 2020

Medicine

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Class I phosphoinositide 3-kinase (PI3K) regulatory subunits and their roles in signaling and disease

Cited by 73 publications

References 88 publications

CircHIPK3/miR-876-5p/PIK3R1 axis regulates regulation proliferation, migration, invasion, and glutaminolysis in gastric cancer cells

CircHIPK3/miR-876-5p/PIK3R1 axis regulates regulation proliferation, migration, invasion, and glutaminolysis in gastric cancer cells

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

Investigating potential molecular mechanisms of serum exosomal miRNAs in colorectal cancer based on bioinformatics analysis

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