Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a ...transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular signaling pathways associated with inflammatory responses, cell proliferation, differentiation and survival. p38β, a member of p38MAPK family, is closely correlated with tumorigenesis, but the mechanism of activation remains unclear. In this study, we found overexpression of Pokemon promoted the growth, migration and invasion of HepG2 cells. However, a p38 inhibitor SB202190 efficiently attenuated the promoting effect of Pokemon in the HepG2 cells. Targeted expression or silencing of Pokemon changed cellular p38β protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38β is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells.
Transforming growth factor-beta (TGF-beta) signals through receptor serine/threonine kinases and intracellular Smad effectors, regulating numerous epithelial cell processes. TGF-beta plays a crucial ...role in the cancer initiation and progression through tumor cell autonomous signaling and interactions with tumor microenvironment, but is featured with a butterfly effect upon the stages of tumorigenesis. TGF-beta signaling acts as a suppressor of epithelial cell tumorigenesis at early stages, but promotes tumor progression by enhancing migration, invasion, and survival of the tumor cells during the later stages. TGF-beta signaling also cross-talks with other cell survival signaling pathways. Tumor microenvironment contains many distinct cell types, which substantially influences the tumor cell growth and survival, and the invasion and metastasis. TGF-beta in the microenvironment, produced by cancer and/or stromal cells, is high and negatively correlates with disease progression and patient prognosis. Therefore, TGF-beta may affect tumor progression by multiple mechanisms in addition to its direct action on tumor cells, and the diversities of TGF-beta signaling in tumors imply a need for caution to TGF-beta-targeted strategies of tumor prevention and/or therapeutics.
Aldo-keto reductase 1 member B1 (AKR1B1) is pathogenically involved in diabetic complications by driving glucose flux through polyol pathway; a variety of AKR1B1 inhibitors has been developed for the ...treatment of diabetic complications and a body of invaluable preclinical and clinical data have been collected through decades' efforts. Recent studies have shown that some AKR1B1 inhibitors demonstrate strong inhibitory activity to aldo-keto reductase family 1 member B10 (AKR1B10), a protein identical to AKR1B1, in vitro and in cancer cells. AKR1B1 and AKR1B10 are overexpressed in human tumors, such as liver, breast, and lung cancer, and may play a critical role in the development and progression of cancer through carbonyl detoxification, retinoic acid homeostatic regulation, and lipid metabolic control, as well as the activation of tobacco smoke carcinogens. Therefore, AKR1B1 inhibitors may represent a novel class of antitumor agents; and the clinical data assembled in diabetic clinics would greatly assist the transition of these inhibitors to cancer clinics. This article summaries the current understanding of the expression and function of AKR1B1 and AKR1B10 in human cancers and reviews the patents and papers of AKR1B1 inhibitors. Authors' opinions concerning the current and future development of AKR1B1 and/or AKR1B10-specific inhibitors are discussed.
We previously isolated cacalol as a free radical-scavenging compound from
Cacalia delphiniifolia
which is a traditional Asian herbal plant and is believed to have medicinal effects on cancer. In this ...report, we demonstrated that cacalol has strong anti-proliferation effect on breast cancer cells and induces apoptosis by activating a pro-apoptotic pathway. We also found that a combination of cacalol and other chemotherapeutic drugs (Taxol and cyclophosphamide) synergistically induced apoptosis and partially overcame chemo-resistance. To further gain a mechanistic insight, we tested a potential inhibitory effect of cacalol on fatty acid synthase gene (FAS) in breast cancer cells, and found that cacalol significantly modulated the expression of the FAS gene, which resulted in apoptosis through activation of DAPK2 and caspase 3. We have also shown that cacalol significantly suppressed the Akt-sterol regulatory element-binding proteins (SREBP) signaling pathway and concomitant transcriptional activation of FAS. In a xenograft model of nude mouse, when cacalol was administered intraperitoneally, tumor growth was significantly suppressed. Importantly, oral administration of cacalol before implanting tumors showed significant preventive effect on tumor growth in the same animal model. Furthermore, the treatment of mice with a combination of low dose of Taxol and cacalol significantly suppressed the tumor growth. Taken together, our results indicate that cacalol induces apoptosis in breast cancer cells and impairs mammary tumor growth in vivo by blocking the expression of the FAS gene through modulation of Akt-SREBP pathway, suggesting that cacalol has potential utility as a chemopreventive and chemotherapeutic agent for breast cancer.
Abrogation of uridine phosphorylase (UPase) leads to abnormalities in pyrimidine metabolism and host protection against 5-fluorouracil (5-FU) toxicity. We elucidated the effects on the metabolism and ...antitumor efficacy of 5-FU and capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) in our UPase knockout (UPase(-/-)) model. Treatment with 5-FU (85 mg/kg) or capecitabine (1,000 mg/kg) five days a week for four weeks caused severe toxicity and structural damage to the intestines of wild-type (WT) mice, but not in UPase(-/-) animals. Capecitabine treatment resulted in a 70% decrease in blood cell counts of WT animals, with only a marginal effect in UPase(-/-) mice. UPase expressing colon 38 tumors implanted in UPase(-/-) mice revealed an improved therapeutic efficacy when treated with 5-FU and capecitabine because of the higher maximum tolerated dose for fluoropyrimidines achievable in UPase(-/-) mice. (19)F-MRS evaluation of capecitabine metabolism in tumors revealed similar activation of the prodrug in UPase(-/-) mice compared with WT. In WT mice, approximately 60% of capecitabine was transformed over three hours into its active metabolites, whereas 80% was transformed in tumors implanted in UPase(-/-) mice. In UPase(-/-) mice, prolonged retention of 5'dFUR allowed a proportional increase in tumor tissue. The similar presence of fluorinated catabolic species confirms that dihydropyrimidine dehydrogenase activity was not altered in UPase(-/-) mice. Overall, these results indicate the importance of UPase in the activation of fluoropyrimidines, the effect of uridine in protecting normal tissues, and the role for tumor-specific modulation of the phosphorolytic activity in 5-FU or capecitabine-based chemotherapy.
We have identified a novel human protein that is highly homologous to aldose reductase (AR). This protein, which we called
ARL-1, consists of 316 amino acids, the same size as AR, and its amino acid ...sequence is 71% identical to that of AR. It is
more closely related to the AR-like proteins such as mouse vas deferens protein, fibroblast growth factor-regulated protein,
and Chinese hamster ovary reductase, with 81, 82, and 83%, respectively, of its amino acid sequence identical to the amino
acid sequence of these proteins. The cDNA of ARL-1 was expressed in Escherichia coli to obtain recombinant protein for characterization of its enzymatic activities. For comparison, the cDNA of human AR was
also expressed in E. coli and analyzed in parallel. These two enzymes differ in their pH optima and salt requirement, but they act on a similar spectrum
of substrates. Similar to AR, ARL-1 can efficiently reduce aliphatic and aromatic aldehydes, and it is less active on hexoses.
While AR mRNA is found in most tissues studied, ARL-1 is primarily expressed in the small intestines and in the colon, with a low level of its mRNA in the liver. The ability of
ARL-1 to reduce various aldehydes and the locations of expression of this gene suggest that it may be responsible for detoxification
of reactive aldehydes in the digested food before the nutrients are passed on to other organs. Interestingly, ARL-1 and AR are overexpressed in some liver cancers, but it is not clear if they contribute to the pathogenesis of this disease.
Background and Aims
A large-scale multicenter study validated aldo–keto reductase 1B10 (AKR1B10) as a new serum marker of hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic ...value of serum AKR1B10 in HCC.
Methods
273 naïve HCC patients enrolled for serum AKR1B10 tests were followed up for 2 years. Survival and clinical data were collected. Kaplan–Meier survival analysis and log-rank tests were used to estimate correlation of patient survival with serum AKR1B10. Univariate and multivariate COX regression analyses were used to evaluate the prognostic value of serum AKR1B10 level independently or in combination with other clinicopathological factors. α-fetoprotein (AFP) was analyzed in parallel for comparison.
Results
Serum AKR1B10 associated with tumor stage (
p =
0.012), size (
p =
0.004), primary tumor number (
p =
0.019), and Child–Pugh classification (
p =
0.003). HCC patients with a high level of serum AKR1B10 (≥ 267.9 pg/ml) had median survival (MS) of 25 months (95% confidence interval CI 20.788–29.212) vs. MS of 34 months (CI 28.911–39.089) in patients with normal serum AKR1B10 (
p <
0.001). Univariate and multivariate COX regression analyses showed that serum AKR1B10 level was an unfavorable prognostic marker of HCC independently (HR 1.830, 95% CI 1.312–2.552;
p <
0.001) or in combination with other clinical factors (HR 1.883, 95% CI 1.264–2.806;
p =
0.002), such as TNM stage, tumor size and portal invasion. In the same cohort of HCC patients, AFP exhibited prognostic value at a cut-off of 400 ng/ml, but not at 20 ng/ml and 200 ng/ml.
Conclusions
Serum AKR1B10 is a new prognostic marker of HCC, better than AFP.
The origin of cancer stem cells Bu, Yiwen; Cao, Deliang
Frontiers in bioscience (Scholar edition),
01/2012, Letnik:
4, Številka:
3
Journal Article
Recenzirano
Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are cancer cells that possess capability of proliferation, differentiation, and self-renewal. It is widely believed that CSCs ...play critical role in the initiation, metastasis, and relapse of cancers, but the origin of CSCs remains unclear. Up to date, several hypotheses have been described, and cell fusion and horizontal gene transfer, which may occur during development and tissue repair process, are considered as important origins of CSCs. In addition, critical gene mutations in stem cells, progenitor cells or even differentiated cells may also contribute to the formation of CSCs, and cell microenvironment is critical to CSC self-renewal and differentiation. The ongoing efforts to identify the CSCs origins may shed more light on understanding of cancer initiation and progression, as well as the development of novel cancer therapies.
We report in the present study the critical role of uridine phosphorylase (UPase) in uridine homeostatic regulation and pyrimidine nucleotide metabolism, employing newly developed UPase–/– mice. Our ...data demonstrate that the abrogation of UPase activity led to greater than a 6-fold increase in uridine concentrations in plasma, a 5–6-fold increase in lung and gut, and a 2–3-fold increase in liver and kidney, as compared with wild type mice. Urine uridine levels increased 24-fold normal in UPase–/– mice. Uridine half-life and the plasma retention of pharmacological doses of uridine were significantly prolonged. Further, in these UPase–/– mice, abnormal uridine metabolism led to disorders of various nucleotide metabolisms. In the liver, gut, kidney, and lung of UPase–/– mice, total uridine ribonucleotide concentrations increased 2–3 times as compared with control mice. Cytidine ribonucleotides and adenosine and guanosine ribonucleotides also increased, although to a lesser extent, in these organs. Most significant deoxyribonucleotide changes were present in the gut and lung of UPase–/– mice. In these tissues, dTTP concentration increased more than 4-fold normal, and dCTP, dGTP, and dATP concentrations rose 1–2 times normal. In kidney, dTTP concentration increased 2-fold normal, and dCTP and dGTP concentrations rose less than 1-fold normal. In addition, the accumulated uridine in plasma and tissues efficiently reduced 5-fluorouracil host toxicity and altered the anesthetic effect of pentobarbital. These data indicate that UPase is a critical enzyme in the regulation of uridine homeostasis and pyrimidine nucleotide metabolism, and 5-fluorouracil activity.
Lipid Metabolism and Immune Checkpoints Liao, Qianjin; Zhou, Yujuan; Xia, Longzheng ...
Advances in experimental medicine and biology,
01/2021, Letnik:
1316
Journal Article
Recenzirano
Immune checkpoints are essential for the regulation of immune cell functions. Although the abrogation of immunosurveillance of tumor cells is known, the regulators of immune checkpoints are not ...clear. Lipid metabolism is one of the important metabolic activities in organisms. In lipid metabolism, a large number of metabolites produced can regulate the gene expression and activation of immune checkpoints through various pathways. In addition, increasing evidence has shown that lipid metabolism leads to transient generation or accumulation of toxic lipids that result in endoplasmic reticulum (ER) stress and then regulate the transcriptional and posttranscriptional modifications of immune checkpoints, including transcription, protein folding, phosphorylation, palmitoylation, etc. More importantly, the lipid metabolism can also affect exosome transportation of checkpoints and the degradation of checkpoints by affecting ubiquitination and lysosomal trafficking. In this chapter, we mainly empathize on the roles of lipid metabolism in the regulation of immune checkpoints, such as gene expression, activation, and degradation.
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