Supplementary Figure from The Impact of PIK3R1 Mutations and Insulin–PI3K–Glycolytic Pathway Regulation in Prostate Cancer
Goutam ChakrabortySubhiksha NandakumarRahim HiraniBastien NguyenKonrad H. StopsackChristoph KreitzerSai Harisha RajanalaRomina GhaleYing Z. MazzuNagavarakishore PillarsettyGwo‐Shu Mary LeeHoward I. ScherMichael J. MorrisTiffany A. TrainaPedram RazaviWassim AbidaJeremy C. DurackStephen B. SolomonMatthew G. Vander HeidenLorelei A. MucciAndreas G. WibmerNikolaus SchultzPhilip W. Kantoff
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Supplementary Figure from The Impact of PIK3R1 Mutations and Insulin–PI3K–Glycolytic Pathway Regulation in Prostate CancerThe phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (Akt)/mammalian target of the rapamycin (mTOR)-signaling pathway has been suggested to have connections with the malignant transformation, growth, proliferation, and metastasis of various cancers and solid tumors. Relevant connections between the PI3K/Akt/mTOR pathway, cell survival, and prostate cancer (PC) provide a great therapeutic target for PC prevention or treatment. Recent studies have focused on small-molecule mTOR inhibitors or their usage in coordination with other therapeutics for PC treatment that are currently undergoing clinical testing. In this study, the function of the PI3K/Akt/mTOR pathway, the consequence of its dysregulation, and the development of mTOR inhibitors, either as an individual substance or in combination with other agents, and their clinical implications are discussed. The rationale for targeting the PI3K/Akt/mTOR pathway, and specifically the application and potential utility of natural agents involved in PC treatment is described. In addition to the small-molecule mTOR inhibitors, there are evidence that several natural agents are able to target the PI3K/Akt/mTOR pathway in prostatic neoplasms. These natural mTOR inhibitors can interfere with the PI3K/Akt/mTOR pathway through multiple mechanisms; however, inhibition of Akt and suppression of mTOR 1 activity are two major therapeutic approaches. Combination therapy improves the efficacy of these inhibitors to either suppress the PC progression or circumvent the resistance by cancer cells.
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Esophageal squamous cell carcinoma (ESCC), is the most common type of esophageal cancer worldwide, mainly occurring in the Asian esophageal cancer belt, including northern China, Iran, and parts of Africa. Phosphatidlinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway is one of the most important cellular signaling pathways, which plays a crucial role in the regulation of cell growth, differentiation, migration, metabolism and proliferation. In addition, mutations in some molecules of PI3K/Akt/mTOR pathway are closely associated with survival and prognosis in ESCC patients. A large number of studies have found that there are many molecules in ESCC that can regulate the PI3K/Akt/mTOR pathway. Overexpression of these molecules often causes aberrant activation of PI3K/Akt/mTOR pathway. Currently, several effective PI3K/Akt/mTOR pathway inhibitors have been developed, which can play anticancer roles either alone or in combination with other inhibitors. This review mainly introduces the general situation of ESCC, the composition and function of PI3K/Akt/mTOR pathway, and regulatory factors that interact with PI3K/Akt/mTOR signaling pathway. Meanwhile, mutations and inhibitors of PI3K/Akt/mTOR pathway in ESCC are also elucidated.
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Osteoarthritis is characterized by degenerative alterations of articular cartilage including both the degradation of extracellular matrix and the death of chondrocytes. The PI3K/Akt pathway has been demonstrated to involve in both processes. Inhibition of its downstream target NF-kB reduces the degradation of extracellular matrix via decreased production of matrix metalloproteinases while inhibition of mTOR increased autophagy to reduce chondrocyte death. However, mTOR feedback inhibits the activity of the PI3K/Akt pathway and inhibition of mTOR could result in increased activity of the PI3K/Akt/NF-kB pathway. We proposed that the use of dual inhibitors of PI3K and mTOR could be a promising approach to more efficiently inhibit the PI3K/Akt pathway than rapamycin or PI3K inhibitor alone and produce better treatment outcome.
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Widespread invasiveness, represented by the invasion and migration, is the most important characteristic of glioblastoma multiforme (GBM) and is the main reason for therapeutic failure and recurrence of the tumor. Hypoxia is one of the main microenvironment in determining tumor invasiveness. Therefore, intense efforts aimed at improved therapeutics are ongoing to demonstrate the molecular mechanisms governing GBM migration and invasion. This study aims to explore the role of phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and its relationship with hypoxia inducible factor-1α (HIF-1α) in the migration and invasion of human glioblastoma U87 cells under hypoxia. In the study, we found that hypoxia could activate the PI3K/Akt/mTOR pathway associated with the enhancements of the migration and invasion of human glioblastoma U87 cells. When the PI3K/Akt/mTOR pathway and HIF-1α were inhibited by the siRNAs or inhibitors, the migration and invasion of human glioblastoma U87 cells were suppressed. Meanwhile, the expression of HIF-1α could be inhibited by the siRNA or inhibitors of PI3K/Akt/mTOR pathway. The aforementioned results demonstrate that hypoxia could induce enhancements of migration and invasion by activating PI3K/Akt/mTOR pathway by targeting HIF-1α in human glioblastoma U87 cells, which provide a theoretical basis for the treatments of GBM by targeting the PI3K/Akt/mTOR/HIF-1α pathway.
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Osteoarthritis is characterized by degenerative alterations of articular cartilage including both the degradation of extracellular matrix and the death of chondrocytes. The PI3K/Akt pathway has been demonstrated to involve in both processes. Inhibition of its downstream target NF-kB reduces the degradation of extracellular matrix via decreased production of matrix metalloproteinases while inhibition of mTOR increased autophagy to reduce chondrocyte death. However, mTOR feedback inhibits the activity of the PI3K/Akt pathway and inhibition of mTOR could result in increased activity of the PI3K/Akt/NF-kB pathway. We proposed that the use of dual inhibitors of PI3K and mTOR could be a promising approach to more efficiently inhibit the PI3K/Akt pathway than rapamycin or PI3K inhibitor alone and produce better treatment outcome.
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Abstract: The PI3K/Akt/mTOR pathway modulates cell growth, proliferation, metabolism, and movement. Moreover, significant studies have shown that the genes involved in this pathway are frequently activated in human cancer. Observational and computational modeling of the PI3K/AKt/ mTOR pathway inhibitors has been explored in clinical trials. It has been observed that the effectiveness and safety evidence from clinical studies and various inhibitors of this route have been given FDA approval. In this review article, we focused on the processes behind the overactivation of PI3K/Akt/mTOR signaling in cancer and provided an overview of PI3K/Akt/mTOR inhibitors as either individual drugs or a combination of different doses of drugs for different types of cancer. Furthermore, the review discusses the biological function and activation of the PI3K/AKt/mTOR signaling and their role in the development of cancers. Additionally, we discussed the potential challenges and corresponding prediction biomarkers of response and resistance for PI3K/Akt/m- TOR inhibitor development. The article focuses on the most current breakthroughs in using the PI3K/Akt/mTOR pathway to target certain molecules.
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The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) pathway regulates numerous cellular processes such as growth, proliferation, cell cycle progression, motility, adhesion, and angio-genesis, and appears to be constitutively active in a majority of renal cell carcinoma (RCC). The integrity of the pathway is clearly vital to the survival and growth of RCC as pharmacologic inhibition of PI3K or Akt induces apoptosis in RCC tumor cells and tumor regression in vivo. These observations suggest that the PI3K/Akt/ mTOR pathway may be an attractive target for drug development in the treatment of RCC. The recently demonstrated clinical efficacy of inhibitors of mTOR supports this hypothesis and demonstrates the relevance of this pathway in RCC. As Akt activates numerous kinases, transcription factors and other proteins associated with cell growth and survival in addition to mTOR, it is possible even greater clinical responses may be achieved with agents that disrupt the PI3K/Akt/mTOR pathway upstream of mTOR. Concurrent with the development of inhibitors of PI3K or Akt for clinical application are efforts to identify predictive biomarkers of response to agents targeting elements of the PI3K/Akt/mTOR pathway so as to develop more individualized patient selection strategies. In this chapter, we will review the molecular biology of the PI3K/Akt/mTOR pathway, its relevance to RCC, and its potential as a therapeutic target in RCC.
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