Artificial intelligence in oncology Shimizu, Hideyuki; Nakayama, Keiichi I.
Cancer science,
20/May , Letnik:
111, Številka:
5
Journal Article
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Artificial intelligence (AI) has contributed substantially to the resolution of a variety of biomedical problems, including cancer, over the past decade. Deep learning, a subfield of AI that is ...highly flexible and supports automatic feature extraction, is increasingly being applied in various areas of both basic and clinical cancer research. In this review, we describe numerous recent examples of the application of AI in oncology, including cases in which deep learning has efficiently solved problems that were previously thought to be unsolvable, and we address obstacles that must be overcome before such application can become more widespread. We also highlight resources and datasets that can help harness the power of AI for cancer research. The development of innovative approaches to and applications of AI will yield important insights in oncology in the coming decade.
Artificial intelligence (AI) has contributed substantially to the resolution of a variety of biomedical problems, including cancer, over the past decade. In this review, we describe numerous recent examples of the application of AI in oncology, including cases in which deep learning has efficiently solved problems that were previously thought to be unsolvable, and we address obstacles that must be overcome before such application can become more widespread.
FBXW7 (also known as Fbw7, Sel10, hCDC4, or hAgo) is a tumor suppressor and the most frequently mutated member of the F-box protein family in human cancers. FBXW7 functions as the substrate ...recognition component of an SCF-type E3 ubiquitin ligase. It specifically controls the proteasome-mediated degradation of many oncoproteins such as c-MYC, NOTCH, KLF5, cyclin E, c-JUN, and MCL1. In this review, we summarize the molecular and biological features of FBXW7 and its substrates as well as the impact of mutations of FBXW7 on cancer development. We also address the clinical potential of anticancer therapy targeting FBXW7.
In the mammalian circadian clockwork, CRY1 and CRY2 repressor proteins are regulated by posttranslational modifications for temporally coordinated transcription of clock genes. Previous studies ...revealed that FBXL3, an F-box-type E3 ligase, ubiquitinates CRYs and mediates their degradation. Here, we found that FBXL21 also ubiquitinates CRYs but counteracts FBXL3. Fbxl21−/− mice exhibited normal periodicity of wheel-running rhythms with compromised organization of daily activities, while an extremely long-period phenotype of Fbxl3−/− mice was attenuated in Fbxl3/Fbxl21 double-knockout mice. The double knockout destabilized the behavioral rhythms progressively and sometimes elicited arrhythmicity. Surprisingly, FBXL21 stabilized CRYs and antagonized the destabilizing action by FBXL3. Predominantly cytosolic distribution of FBXL21 contrasts with nuclear localization of FBXL3. These results emphasize the physiological importance of antagonizing actions between FBXL21 and FBXL3 on CRYs, and their combined actions at different subcellular locations stabilize oscillation of the circadian clock.
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► FBXL21 stabilizes CRY1 and CRY2, key players in the circadian clockwork ► FBXL21 action antagonizes the destabilizing action of FBXL3 on CRYs ► Depletion of Fbxl21/Fbxl 3 destabilized behavioral rhythm or caused arrhythmicity ► FBXL21 and FBXL3 actions are vital for robustness of the circadian clock oscillation.
FBXL21, an F-box-type ubiquitin E3 ligase, is identified as a regulator of the circadian clock repressor CRYPTOCHROME (CRY) proteins. FBXL21 has the opposite effects on circadian period and CRY stability compared to its homolog, FBXL3, and their combined actions at different subcellular locations ensures stable oscillation of the circadian clock.
Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, ...we identified glutaminase 1 (
) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.
Mechanistic target of rapamycin complex 1 (mTORC1) is a serine-threonine kinase that is activated by extracellular signals, such as nutrients and growth factors. It plays a key role in the control of ...various biological processes, such as protein synthesis and energy metabolism by mediating or regulating the phosphorylation of multiple target molecules, some of which remain to be identified. We have here reanalysed a large-scale phosphoproteomics data set for mTORC1 target molecules and identified pre-B cell leukemia transcription factor 2 (PBX2) as such a novel target that is dephosphorylated downstream of mTORC1. We confirmed that PBX2, but not other members of the PBX family, is dephosphorylated in an mTORC1 activity-dependent manner. Furthermore, pharmacological and gene knockdown experiments revealed that glycogen synthase kinase 3 (GSK3) and protein phosphatase 1 (PP1) are responsible for the phosphorylation and dephosphorylation of PBX2, respectively. Our results thus suggest that the balance between the antagonistic actions of GSK3 and PP1 determines the phosphorylation status of PBX2 and its regulation by mTORC1.
Glucose metabolism is remodeled in cancer, but the global pattern of cancer-specific metabolic changes remains unclear. Here we show, using the comprehensive measurement of metabolic enzymes by ...large-scale targeted proteomics, that the metabolism both carbon and nitrogen is altered during the malignant progression of cancer. The fate of glutamine nitrogen is shifted from the anaplerotic pathway into the TCA cycle to nucleotide biosynthesis, with this shift being controlled by glutaminase (GLS1) and phosphoribosyl pyrophosphate amidotransferase (PPAT). Interventions to reduce the PPAT/GLS1 ratio suppresses tumor growth of many types of cancer. A meta-analysis reveals that PPAT shows the strongest correlation with malignancy among all metabolic enzymes, in particular in neuroendocrine cancer including small cell lung cancer (SCLC). PPAT depletion suppresses the growth of SCLC lines. A shift in glutamine fate may thus be required for malignant progression of cancer, with modulation of nitrogen metabolism being a potential approach to SCLC treatment.
Carbon and nitrogen are essential elements for life. Glucose as a carbon source and glutamine as a nitrogen source are important nutrients for cell proliferation. About 100 years ago, it was ...discovered that cancer cells that have acquired unlimited proliferative capacity and undergone malignant evolution in their host manifest a cancer-specific remodeling of glucose metabolism (the Warburg effect). Only recently, however, was it shown that the metabolism of glutamine-derived nitrogen is substantially shifted from glutaminolysis to nucleotide biosynthesis during malignant progression of cancer-which might be referred to as a "second" Warburg effect. In this review, address the mechanism and relevance of this metabolic shift of glutamine-derived nitrogen in human cancer. We also examine the clinical potential of anticancer therapies that modulate the metabolic pathways of glutamine-derived nitrogen. This shift may be as important as the shift in carbon metabolism, which has long been known as the Warburg effect.
Although the definition of a noncoding RNA (ncRNA) is an RNA molecule that does not encode a protein, recent evidence has revealed that some ncRNAs are indeed translated to give rise to small ...polypeptides (usually containing fewer than 100 amino acids). Despite their small size, however, these peptides are often biologically relevant in that they are required for a variety of cellular processes. In this review, we summarize the production and functions of peptides that have been recently identified as translation products of putative ncRNAs.Key words: long noncoding RNA (lncRNA), circular RNA (circRNA), primary miRNA (pri-miRNA), translation, peptide
Quiescence is required for the maintenance of hematopoietic stem cells (HSCs). Members of the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors (p21, p27, p57) have been implicated in HSC ...quiescence, but loss of p21 or p27 in mice affects HSC quiescence or functionality only under conditions of stress. Although p57 is the most abundant family member in quiescent HSCs, its role has remained uncharacterized. Here we show a severe defect in the self-renewal capacity of p57-deficient HSCs and a reduction of the proportion of the cells in G
0 phase. Additional ablation of p21 in a p57-null background resulted in a further decrease in the colony-forming activity of HSCs. Moreover, the HSC abnormalities of p57-deficient mice were corrected by knocking in the
p27 gene at the
p57 locus. Our results therefore suggest that, among Cip/Kip family CDK inhibitors, p57 plays a predominant role in the quiescence and maintenance of adult HSCs.
► p57 is the most abundant CDK inhibitor in quiescent hematopoietic stem cells (HSCs) ► p57 deficiency in hematopoietic cells resulted in a decrease in the HSC population ► p57-deficient HSCs lost the ability to reconstitute the hematopoietic system ► Maintenance of quiescence was defective in p57-deficient HSCs
Iron-dependent degradation of iron-regulatory protein 2 (IRP2) is a key event for maintenance of an appropriate intracellular concentration of iron. Although FBXL5 (F box and leucine-rich repeat ...protein 5) is thought to mediate this degradation, the role of FBXL5 in the control of iron homeostasis in vivo has been poorly understood. We have now found that mice deficient in FBXL5 died in utero, associated with excessive iron accumulation. This embryonic mortality was prevented by additional ablation of IRP2, suggesting that impaired IRP2 degradation is primarily responsible for the death of Fbxl5−/− mice. We also found that liver-specific deletion of Fbxl5 resulted in deregulation of both hepatic and systemic iron homeostasis, leading to the development of steatohepatitis. The liver-specific mutant mice died with acute liver failure when fed a high-iron diet. Thus, our results uncover a major role for FBXL5 in ensuring an appropriate supply of iron to cells.
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► Fbxl5−/− mice die in utero, manifesting IRP2 accumulation ► Additional ablation of IRP2 prevents the death of Fbxl5−/− embryos ► Liver-specific Fbxl5 mutant mice develop steatohepatitis and impaired iron metabolism ► Liver-specific Fbxl5 mutant mice die with acute liver failure on a high-iron diet
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