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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The serine/threonine kinase Akt, named after a strain of mice and also known as Protein Kinase B (PKB), has a critical role in the PI3K-Akt signaling pathway (Figure 6.87) which is involved in a number of cellular processes including proliferation, survival, glucose metabolism, genome stability, transcription, protein synthesis, and neovascularization. Inhibition of Akt results in a reduction in cell-cycle progression and tumor growth. Akt has three isoforms, Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ), all of which share high sequence homology and are composed of similar structural domains. The catalytic structural domain has highly homology with Protein Kinases A (PKA) and C (PKC), and other cAMP-dependent protein kinases.
Developmental Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James H. Tonsgard, Nikolas Mata-Machado
HI is believed to be due to a somatic cell mosaicism involving pigmentary genes. However, a variety of mosaic chromosomal abnormalities have also been reported including trisomy 18, triploidy, and tetrasomy 12p, and mutations in the X chromosome. It is hypothesized that the chromosomal anomalies disrupt expression or function of pigmentary genes. Pigmentary genes control a variety of processes, including melanoblast migration from the neural crest in fetal life. It is suggested that the pigmentary pattern that follows Blaschko's lines is the result of the migration of two different clones of cells during embryogenesis. The complex malformation of HI is postulated to be due to somatic genetic changes early in development, whereas patients with isolated skin manifestations are felt to be due to somatic changes in the skin alone, later in development. Mutations in the PI3K-AkT3-mTOR pathway have been seen in some patients.
Micronutrients in Prevention and Improvement of the Standard Therapy in Hearing Disorders
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Although increased oxidative stress is involved in the pathogenesis of hearing disorders, only a few studies are available on the effects of this biochemical event on changes in the expression of miRs in the cochlear hair cells. Increased oxidative stress induced by t-BHP (tert-butylhydroperoxide) enhanced the expression of 24 microRNAs. Among these, 6 microRNAs: miR-1934, miR-411, miR-717, miR-503, miR-467e, and miR-699o that regulate apoptosis and proliferation of the cochlear hair cells were strongly expressed.125 ROS generated by the treatment with t-BHO increased the expression of 35 microRNAs and decreased the expression of 40 microRNAs, and inhibited the proliferation of hair cells (HE1-C1).126Reactive oxygen species (ROS) generated by exposure to ionizing radiation enhanced the expression of miR-207 in the hair cell line (HE1-OC1). This microRNA increased radiation-induced apoptosis and DNA damage by inhibiting its target protein AKt3. This was further supported by the fact that inhibiting the levels of AKt3 mimicked the effects of miR-207.127In diabetic mice with a high level of internal oxidative stress, the expression of miR-34a was elevated and the level of SIRT1 was inhibited and promoted apoptosis in the hair cells (HE1-OC1). This finding indicated that downregulation of miR-34a may help in diabetic-related hearing loss.128
Overexpression of miR-181a regulates the Warburg effect in triple-negative breast cancer
Published in Climacteric, 2023
Y. Wang, H. Tahiri, C. Yang, M. Gu, X. Ruan, P. Hardy
In an oxygen-adequate environment, normal (non-neoplastic) cells generate most of their energy in the form of ATP by a process known as oxidative phosphorylation. When oxygen is in limited supply, normal cells are also capable of metabolizing glucose into pyruvate which generates both ATP and lactic acid [5,6]. In the early twentieth century, the German biochemist Otto Warburg found that tumor tissues exhibit unexpectedly high rates of glucose uptake and lactate production even in environments with adequate oxygen, a phenomenon known as the ‘Warburg effect’ [7]. This effect permits tumor cells to adjust their energy production mechanisms to support growth, metastasis, survival and drug resistance, among others [6,7]. Notably, results from recent studies have implicated the transcription factor hypoxia-inducible factor-1 (HIF-1), protein kinase B (AKT) and microRNAs (miRNAs) in the regulation of aerobic glycolysis in cancer tissues [8]. HIF-1 is a heterodimeric oxygen-sensitive transcription factor that includes the constitutively expressed subunit HIF-1β in a complex with an oxygen-regulated subunit HIF-1α [9]. AKT is a serine/threonine kinase with three isoforms (AKT1, AKT2 and AKT3) [10]. miRNAs are endogenous non-coding regulatory RNAs typically 20–24 nucleotides in length [11] that bind to specific 3′ untranslated region sequences and target gene expression at the post-transcriptional level. miRNA deregulation is a common characteristic of numerous human cancers [11,12].
Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Dima A. Sabbah, Rima Hajjo, Sanaa K. Bardaweel, Haizhen A. Zhong
Mutations and aberrations of AKT isoforms have been identified in multiple human cancers [6]. AKT regulates cancer growth, metabolism, metastasis, and angiogenesis. Three AKT isoforms are extracted from three discrete genes [6]. AKT1 was shown to be overexpressed in stomach cancers [6]. AKT1 mutations have been detected in 8% breast cancers, 6% colon cancers, and 2% ovarian cancers [6]. Overexpression of AKT2 has been recorded in pancreatic, ovarian, and colon cancers [6]. Studies have reported that impairment of AKT2 inhibits the invasiveness of colorectal carcinoma cell lines. Somatic mutations in AKT3 have been detected in melanomas. Studies have shown that AKT3 mRNA is overexpressed in estrogen receptor (ER)-negative breast cancers [6]. Eventually, design and development of selective inhibitors targeting PI3K/AKT/mTOR and their effectors represents a new trend in anti-cancer research.
LINC02163 promotes colorectal cancer progression via miR-511-3p/AKT3 axis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Junwen Ma, Lihai Zhang, Anquan Shang, Hu Song, Jiege Huo, Mingjian Zhang, Liuqin Jiang
AKT3 is a member of the AKT family, which takes key roles in a variety of cell growth processes, such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration [25]. AKT3 has been demonstrated as oncogenes in CRC through PI3K/AKT signalling pathway [26]. In our study, we found that AKT3 was upregulated in CRC patients and positively correlated with the abundance of LINC02163 in CRC tissues, indicating the pro-tumoral role of AKT3 in CRC (Figure 5(A,B)). Additionally, both mRNA and protein level of AKT3 in CRC cells transduced with sh-LINC02163 were greatly rescued by miR-511-3p inhibitor transfection (Figure 5(C,D)). Cell proliferation assays displayed CRC cells growth was elevated by inhibition of miR-511-3p or overexpression of AKT3 (Figure 5(E,F)). As for mechanism investigation, knockdown of LINC02163 led to cell cycle arrest in G0/G1 stage while transfection of miR-511-3p or AKT3 abolished cycle arrest in LINC02163-depletion CRC cells, indicating LINC02163 promoted cell proliferation through modifying cell cycle progress (Figure 5(G)).