Role of AKR1B10 in inflammatory diseases.

Inflammation is an important pathophysiological process in many diseases; it has beneficial and harmful effects. When exposed to various stimuli, the body triggers an inflammatory response to eliminate invaded pathogens and damaged tissues to maintain homeostasis. However, uncontrollable persistent or excessive inflammatory responses may damage tissues and induce various diseases, such as metabolic diseases (e.g. diabetes), autoimmune diseases, nervous system-related diseases, digestive system-related diseases, and even tumours. Aldo-keto reductase 1B10 (AKR1B10) is an important player in the development and progression of multiple diseases, such as tumours and inflammatory diseases. AKR1B10 is upregulated in solid tumours, such as hepatocellular carcinoma (HCC), non-small cell lung carcinoma, and breast cancer, and is a reliable serum marker. However, information on the role of AKR1B10 in inflammation is limited. In this study, we summarized the role of AKR1B10 in inflammatory diseases, including its expression, functional contribution to inflammatory responses, and regulation of signalling pathways related to inflammation. We also discussed the role of AKR1B10 in glucose and lipid metabolism and oxidative stress. This study provides novel information and increases the understanding of clinical inflammatory diseases.

Nicotinate-curcumin improves NASH by inhibiting the AKR1B10/ACCα-mediated triglyceride synthesis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a prevalent chronic liver condition. However, the potential therapeutic benefits and underlying mechanism of nicotinate-curcumin (NC) in the treatment of NASH remain uncertain. METHODS: A rat model of NASH induced by a high-fat and high-fructose diet was treated with nicotinate-curcumin (NC, 20, 40 mg·kg- 1), curcumin (Cur, 40 mg·kg- 1) and metformin (Met, 50 mg·kg- 1) for a duration of 4 weeks. The interaction between NASH, Cur and Aldo-Keto reductase family 1 member B10 (AKR1B10) was filter and analyzed using network pharmacology. The interaction of Cur, NC and AKR1B10 was analyzed using molecular docking techniques, and the binding energy of Cur and NC with AKR1B10 was compared. HepG2 cells were induced by Ox-LDL (25 µg·ml- 1, 24 h) in high glucose medium. NC (20µM, 40µM), Cur (40µM) Met (150µM) and epalrestat (Epa, 75µM) were administered individually. The activities of ALT, AST, ALP and the levels of LDL, HDL, TG, TC and FFA in serum were quantified using a chemiluminescence assay. Based on the changes in the above indicators, score according to NAS standards. The activities of Acetyl-CoA and Malonyl-CoA were measured using an ELISA assay. And the expression and cellular localization of AKR1B10 and Acetyl-CoA carboxylase (ACCα) in HepG2 cells were detected by Western blotting and immunofluorescence. RESULTS: The results of the animal experiments demonstrated that NASH rat model induced by a high-fat and high-fructose diet exhibited pronounced dysfunction in liver function and lipid metabolism. Additionally, there was a significant increase in serum levels of FFA and TG, as well as elevated expression of AKR1B10 and ACCα, and heightened activity of Acetyl-CoA and Malonyl-CoA in liver tissue. The administration of NC showed to enhance liver function in rats with NASH, leading to reductions in ALT, AST and ALP levels, and decrease in blood lipid and significant inhibition of FFA and TG synthesis in the liver. Network pharmacological analysis identified AKR1B10 and ACCα as potential targets for NASH treatment. Molecular docking studies revealed that both Cur and NC are capable of binding to AKR1B10, with NC exhibiting a stronger binding energy to AKR1B10. Western blot analysis demonstrated an upregulation in the expression of AKR1B10 and ACCα in the liver tissue of NASH rats, accompanied by elevated Acetyl-CoA and Malonyl-CoA activity, and increased levels of FFA and TG. The results of the HepG2 cell experiments induced by Ox-LDL suggest that NC significantly inhibited the expression and co-localization of AKR1B10 and ACCα, while also reduced levels of TC and LDL-C and increased level of HDL-C. These effects are accompanied by a decrease in the activities of ACCα and Malonyl-CoA, and levels of FFA and TG. Furthermore, the impact of NC appears to be more pronounced compared to Cur. CONCLUSION: NC could effectively treat NASH and improve liver function and lipid metabolism disorder. The mechanism of NC is related to the inhibition of AKR1B10/ACCα pathway and FFA/TG synthesis of liver.

A Comprehensive Review on the Benefits and Problems of Curcumin with Respect to Human Health.

Curcumin is the most important active component in turmeric extracts. Curcumin, a natural monomer from plants has received a considerable attention as a dietary supplement, exhibiting evident activity in a wide range of human pathological conditions. In general, curcumin is beneficial to human health, demonstrating pharmacological activities of anti-inflammation and antioxidation, as well as antitumor and immune regulation activities. Curcumin also presents therapeutic potential in neurodegenerative, cardiovascular and cerebrovascular diseases. In this review article, we summarize the advancements made in recent years with respect to curcumin as a biologically active agent in malignant tumors, Alzheimer's disease (AD), hematological diseases and viral infectious diseases. We also focus on problems associated with curcumin from basic research to clinical translation, such as its low solubility, leading to poor bioavailability, as well as the controversy surrounding the association between curcumin purity and effect. Through a review and summary of the clinical research on curcumin and case reports of adverse effects, we found that the clinical transformation of curcumin is not successful, and excessive intake of curcumin may have adverse effects on the kidneys, heart, liver, blood and immune system, which leads us to warn that curcumin has a long way to go from basic research to application transformation.

Lipid Metabolism and Immune Checkpoints.

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.

A Large-Scale Multicenter Study Validates Aldo-Keto Reductase Family 1 Member B10 as a Prevalent Serum Marker for Detection of Hepatocellular Carcinoma.

Aldo-keto reductase family 1 member B10 (AKR1B10) is a secretory protein overexpressed in hepatocellular carcinoma (HCC). We aimed to evaluate AKR1B10 as a serum marker for detection of HCC. Herein, we conducted a cohort study that consecutively enrolled 1,244 participants from three independent hospitals, including HCC, healthy controls (HCs), benign liver tumors (BLTs), chronic hepatitis B (CHB), and liver cirrhosis (LC). Serum AKR1B10 was tested by time-resolved fluorescent assays. Data were plotted for receiver operating characteristic (ROC) curve analyses. Alpha-fetoprotein (AFP) was analyzed for comparison. An exploratory discovery cohort demonstrated that serum AKR1B10 increased in patients with HCC (1,567.3 ± 292.6 pg/mL; n = 69) compared with HCs (85.7 ± 10.9 pg/mL; n = 66; P < 0.0001). A training cohort of 519 participants yielded an optimal diagnostic cutoff of serum AKR1B10 at 267.9 pg/mL. When ROC curve was plotted for HCC versus all controls (HC + BLT + CHB + LC), serum AKR1B10 had diagnostic parameters of the area under the curve (AUC) 0.896, sensitivity 72.7%, and specificity 95.7%, which were better than AFP with AUC 0.816, sensitivity 65.1%, and specificity 88.9%. Impressively, AKR1B10 showed promising diagnostic potential in early-stage HCC and AFP-negative HCC. Combination of AKR1B10 with AFP increased diagnostic accuracy for HCC compared with AKR1B10 or AFP alone. A validation cohort of 522 participants confirmed these findings. An independent cohort of 68 patients with HCC who were followed up showed that serum AKR1B10 dramatically decreased 1 day after operation and was nearly back to normal 3 days after operation. Conclusion: AKR1B10 is a potent serum marker for detection of HCC and early-stage HCC, with better diagnostic performance than AFP.

Curcumin Nicotinate Selectively Induces Cancer Cell Apoptosis and Cycle Arrest through a P53-Mediated Mechanism.

Curcumin is an anticancer agent, but adverse effects and low bioavailability are its main drawbacks, which drives efforts in chemical modifications of curcumin. This study evaluated antiproliferative activity and cancer cell selectivity of a curcumin derivative, curcumin nicotinate (CN), in which two niacin molecules were introduced. Our data showed that CN effectively inhibited proliferation and clonogenic growth of colon (HCT116), breast (MCF-7) and nasopharyngeal (CNE2, 5-8F and 6-10B) cancer cells with IC50 at 27.7 µM, 73.4 µM, 64.7 µM, 46.3 µM, and 31.2 µM, respectively. In cancer cells, CN induced apoptosis and cell cycle arrest at G2/M phase through a p53-mediated mechanism, where p53 was activated, p21 and pro-apoptotic proteins Bid and Bak were upregulated, and PARP was cleaved. In non-transformed human mammary epithelial cells MCF10A, CN at 50 µM had no cytotoxicity and p53 was not activated, but curcumin at 12.5 µM activated p53 and p21 and inhibited MCF10A cell growth. These data suggest that CN inhibits cell growth and proliferation through p53-mediated apoptosis and cell cycle arrest with cancer cell selectivity.

AKR1B10 activates diacylglycerol (DAG) second messenger in breast cancer cells.

Aldo-keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. However, little is known of the molecular mechanisms of action. Herein we report that AKR1B10 activates lipid second messengers to stimulate cell proliferation. Our data showed that ectopic expression of AKR1B10 in breast cancer cells MCF-7 promoted lipogenesis and enhanced levels of lipid second messengers, including phosphatidylinositol bisphosphate (PIP2), diacylglycerol (DAG), and inositol triphosphate (IP3). In contrast, silencing of AKR1B10 in breast cancer cells BT-20 and colon cancer cells HCT-8 led to decrease of these lipid messengers. Qualitative analyses by liquid chromatography-mass spectrum (LC-MS) revealed that AKR1B10 regulated the cellular levels of total DAG and majority of subspecies. This in turn modulated the phosphorylation of protein kinase C (PKC) isoforms PKCδ (Thr505), PKCµ (Ser744/748), and PKCα/ßII (Thr638/641) and activity of the PKC-mediated c-Raf/MEK/ERK signaling cascade. A pan inhibitor of PKC (Go6983) blocked ERK1/2 activation by AKR1B10. In these cells, phospho-p90RSK, phospho-MSK, and Cyclin D1 expression was increased by AKR1B10, and pharmacological inhibition of the ERK signaling cascade with MEK1/2 inhibitors U0126 and PD98059 eradicated induction of phospho-p90RSK, phospho-MSK, and Cyclin D1. In breast cancer cells, AKR1B10 promoted the clonogenic growth and proliferation of breast cancer cells in two-dimension (2D) and three-dimension (3D) cultures and tumor growth in immunodeficient female nude mice through activation of the PKC/ERK pathway. These data suggest that AKR1B10 stimulates breast cancer cell growth and proliferation through activation of DAG-mediated PKC/ERK signaling pathway.

LncRNAs in DNA damage response and repair in cancer cells.

In order to maintain integrity of the genome, eukaryotic cells develop a complex DNA damage/repair response network, which can induce cell cycle arrest, apoptosis, or DNA repair. Chemo- and radiation therapies, which act primarily through the induction of DNA damage, are the most commonly used therapies for cancer. Impairment in the DNA damage response and repair system that protect cells from persistent DNA damage can affect the therapeutic efficacy of cancer. To date, accumulating evidence has suggested that long non-coding RNAs (lncRNAs) are involved in the regulation of the DNA damage/repair network. LncRNAs have been demonstrated to be master regulators of the genome at the transcriptional and post-transcriptional levels and play a key role in many physiological and pathological processes of cells. In this review, we will discuss the function of lncRNAs in regulating the cellular response to DNA damage.

Aldo-keto reductase 1B10 protects human colon cells from DNA damage induced by electrophilic carbonyl compounds.

Electrophilic carbonyl compounds are highly cytotoxic and genotoxic. Aldo-keto reductase 1B10 (AKR1B10) is an enzyme catalyzing reduction of carbonyl compounds to less toxic alcoholic forms. This study presents novel evidence that AKR1B10 protects colon cells from DNA damage induced by electrophilic carbonyl compounds. AKR1B10 is specifically expressed in epithelial cells of the human colon, but this study found that AKR1B10 expression was lost or markedly diminished in colorectal cancer, precancerous tissues, and a notable portion of normal adjacent tissues (NAT). SiRNA-mediated silencing of AKR1B10 in colon cancer cells HCT-8 enhanced cytotoxicity of acrolein and HNE, whereas ectopic expression of AKR1B10 in colon cancer cells RKO prevented the host cells against carbonyl cytotoxicity. Furthermore, siRNA-mediated AKR1B10 silencing led to DNA breaks and activation of γ-H2AX protein, a marker of DNA double strand breaks, particularly in the exposure of HNE (10 µM). In the AKR1B10 silenced HCT-8 cells, hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutant frequency increased by 26.8 times at basal level and by 33.5 times in the presence of 10 µM HNE when compared to vector control cells. In these cells, the cyclic acrolein-deoxyguanosine adducts levels were increased by over 10 times. These findings were confirmed by pharmacological inhibition of AKR1B10 activity by Epalrestat. Taken together, these data suggest that AKR1B10 is a critical protein that protects host cells from DNA damage induced by electrophilic carbonyl compounds. AKR1B10 deficiency in the colon may be an important pathogenic factor in disease progression and carcinogenesis. © 2016 Wiley Periodicals, Inc.

Exposure of CCRF-CEM cells to acridone derivative 8a triggers tumor death via multiple mechanisms.

A newly synthesized acridone derivative 8a shows potent antitumor activity against CCRF-CEM leukemia cells. Herein, the first proteomic study of 8a effects in CCRF-CEM cells was performed by 2D nano-LC-ESI-MS/MS to better understand the mechanisms of action of 8a. Data analyses based on PLGS, STRING, Cytoscape, and database for annotation, visualization, and integrated discovery identified 55 proteins that were differentially expressed in response to 8a exposure. Multiple cellular pathways were affected, including chromatin organization, energy metabolism, DNA repair, oxidative-stress, and apoptosis. The changes in protein expression were further verified for PKM2. Moreover, 8a lowered down the expression of HEX and PFK-1. Lactate production was decreased in 8a-treated cells, indicating suppression of glycolysis. The elevated XRCC6 and decreased histone expression levels suggested increased DNA damage in 8a-treated cells, which was confirmed by the increased γ-H2AX foci. Molecular docking of 8a with DNA demonstrated direct interactions of 8a with DNA through three hydrogen bonds and four π-π interactions, potentially explaining the mode of action that 8a damaged to DNA. The differential protein profiling and dysfunction of metabolic pathways induced by 8a provide novel insights into the potential action mechanisms of 8a.

A phosphomimetic mutant of RelA/p65 at Ser536 induces apoptosis and senescence: An implication for tumor-suppressive role of Ser536 phosphorylation.

Hundreds of NF-κB inhibitors have been developed for cancer therapy, but their clinical efficacy is unsatisfactory. Here we show that the phosphorylation activation at Ser536 of RelA/p65 protein, a main subunit in the NF-κB family, may play a tumor-suppressive role. In normal colon mucosa, RelA/p65 phosphorylation at Ser536 was increasingly increased with the maturation and apoptotic shedding of epithelial cells, but the phosphorylation at Ser536 was decreased in colon cancer. In colon (HCT116 p53 wt and p53 -/-), breast (MCF7), and prostate (LNCaP and DU145) cancer cells, a phosphomimetic mutation of RelA/p65 at Ser536 (named p65/S536D) triggered dramatic apoptosis through affecting expression of a wide range of cell death/survival genes, such as Bim, Puma, Noxa, Bcl-2 and survivin. In HCT116 cells, p65/S536D mutant upregulated Fas, insulted mitochondrial membrane potential, and triggered cleavage and activation of caspase-3, 7, 8 and 9. A FasL neutralizing antibody (NOK1) prevented cell death induced by the p65/S536D. A pan inhibitor of caspases, Z-VAD-FMK (20 µM), blocked caspase-mediated mitochondrial membrane depolarization. This p65/S536D also triggered senescence in HCT116 cells through a p16-dependent pathway, but not in MFC7 due to lack of p16. Intratumoral delivery of the p65/S536D effectively suppressed tumor growth in nude mice. Together our data suggest that the phosphorylation of RelA/p65 at Ser536 may confer it a tumor-suppressive role by inducing apoptosis and senescence, highlighting the importance of discriminating the function and active status of individual active sites in RelA/p65 when NF-κB inhibitors are considered for targeted therapy of cancer.

Heat shock protein 90-α mediates aldo-keto reductase 1B10 (AKR1B10) protein secretion through secretory lysosomes.

Aldo-keto reductase 1B10 (AKR1B10) protein is a new tumor biomarker in humans. Our previous studies have shown that AKR1B10 is secreted through a lysosome-mediated nonclassical pathway, leading to an increase in the serum of breast cancer patients. This study illuminates the regulatory mechanism of AKR1B10 secretion. The cytosolic AKR1B10 associates with and is translocated to lysosomes by heat shock protein 90α (HSP90α), a chaperone molecule. Ectopic expression of HSP90α significantly increased the secretion of endogenous AKR1B10 and exogenous GFP-AKR1B10 fusion protein when cotransfected. Geldanamycin, a HSP90α inhibitor, dissociated AKR1B10-HSP90α complexes and significantly reduced AKR1B10 secretion in a dose-dependent manner. We characterized the functional domain in AKR1B10 and found that helix 10 (amino acids 233-240), located at the C terminus, regulates AKR1B10 secretion. Targeted point mutations recognized that amino acids Lys-233, Glu-236, and Lys-240 in helix 10 mediate the interaction of AKR1B10 with HSP90α. Together, our data suggest that HSP90α mediates AKR1B10 secretion through binding to its helix 10 domain. This finding is significant in exploiting the use of AKR1B10 in cancer clinics.

Statil suppresses cancer cell growth and proliferation by the inhibition of tumor marker AKR1B10.

Aldo-keto reductase 1B10 (AKR1B10) is an oncogenic carbonyl reductase that eliminates α,ß-unsaturated carbonyl compounds/lipid peroxides and mediates retinoic acid signaling. Targeted inhibition of AKR1B10 activity is a newly emerging strategy for cancer therapy. This study evaluated the inhibitory activity of a small chemical statil towards AKR1B10 and tested its antiproliferative activity in breast (BT-20) and lung (NCI-H460) cancer cells that express AKR1B10. Experimental results showed that statil inhibited AKR1B10 enzyme activity efficiently, with an IC50 at 0.21±0.06 µmol/l. Exposing BT-20 and NCI-H460 cells to statil and diclofenac, a selective AKR1B10 inhibitor, led to dose-dependent inhibition of cell growth and proliferation and plating efficiency. At higher doses (50 µmol/l or higher), statil induced cell death with apoptotic characteristics, such as DNA fragmentation and Annexin-V staining. Furthermore, statil enhanced the susceptibility of cells to acrolein, an active substrate of AKR1B10. Taken together, these data suggest that statil possesses potent antiproliferative activity by inhibiting AKR1B10 activity.

Apoptotic death of cancer stem cells for cancer therapy.

Cancer stem cells (CSCs) play crucial roles in tumor progression, chemo- and radiotherapy resistance, and recurrence. Recent studies on CSCs have advanced understanding of molecular oncology and development of novel therapeutic strategies. This review article updates the hypothesis and paradigm of CSCs with a focus on major signaling pathways and effectors that regulate CSC apoptosis. Selective CSC apoptotic inducers are introduced and their therapeutic potentials are discussed. These include synthetic and natural compounds, antibodies and recombinant proteins, and oligonucleotides.

Interleukin-6 inhibits voltage-gated sodium channel activity of cultured rat spinal cord neurons.

OBJECTIVE: Interleukin-6 (IL-6) is a pleiotropic proinflammatory cytokine that plays a key role in the injuries and diseases of the central nervous system (CNS). A voltage-gated Na+ channel (VGSC) is essential for the excitability and electrical properties of the neurons. However, there is still limited information on the role of IL-6 in voltage-gated sodium channels. Our study aimed to investigate the effects of IL-6 on Na+ currents in cultured spinal-cord neurons. METHODS: VGSC currents were activated and recorded using whole-cell patch-clamp technique in the cultured rat spinal cord neurons. The effects of IL-6 concentration and exposure duration were examined. To determine whether any change in the number of channels in the plasma membrane can inhibit IL-6 on VGSC currents, we examined the expression of α1A (SCN1α) subunit mRNA level and protein level in the neurons before and after IL-6 induction using real-time polymerase chain reaction. RESULTS: We verified that IL-6, through a receptor-mediated mechanism, suppressed Na+ currents in a time- and dose-dependent manner, but did not alter the voltage-dependent activation and inactivation. Gp130 was involved in this inhibition. Furthermore, the spike amplitude was also inhibited by IL-6 in the doses that decreased the Na+ currents. CONCLUSION: VGSC currents are significantly inhibited by IL-6. Our findings reveal that the potential neuroprotection of IL-6 may result from the inhibitory effects on VGSC currents.

Aldo-keto reductase 1B10 as a Carcinogenic but Not a Prognostic Factor in Colorectal Cancer.

Colorectal cancer (CRC) is the leading cause of cancer death, but little is known about its etiopathology. Aldo-keto reductase 1B10 (AKR1B10) protein is primarily expressed in intestinal epithelial cells, but lost in colorectal cancer tissues. This study revealed that AKR1B10 may not be a prognostic but an etiological factor in colorectal tumorigenesis. Using a tissue microarray, we investigated the expression of AKR1B10 in tumor tissues of 592 colorectal cancer patients with a mean follow-up of 25 years. Results exhibited that AKR1B10 protein was undetectable in 374 (63.13%), weakly positive in 146 (24.66%), and positive 72 (12.16%) of 592 tumor tissues. Kaplan-Meier analysis showed that AKR1B10 expression was not correlated with overall survival or disease-free survival. Similar results were obtained in various survival analyses stratified by clinicopathological parameters. AKR1B10 was not correlated with tumor T-pathology, N-pathology, TNM stages, cell differentiation and lymph node/regional/distant metastasis either. However, AKR1B10 silencing in culture cells enhanced carbonyl induced protein and DNA damage; and in ulcerative colitis tissues, AKR1B10 deficiency was associated acrolein-protein lesions. Together this study suggests that AKR1B10 downregulation may not be a prognostic but a carcinogenic factor of colorectal cancer.

Epidermal growth factor induces tumour marker AKR1B10 expression through activator protein-1 signalling in hepatocellular carcinoma cells.

AKR1B10 (aldo-keto reductase 1B10) is overexpressed in liver and lung cancer, and plays a critical role in tumour development and progression through promoting lipogenesis and eliminating cytotoxic carbonyls. AKR1B10 is a secretory protein and potential tumour marker; however, little is known about the regulatory mechanism of AKR1B10 expression. The present study showed that AKR1B10 is induced by mitogen EGF (epidermal growth factor) and insulin through the AP-1 (activator protein-1) signalling pathway. In human HCC (hepatocellular carcinoma) cells (HepG2 and Hep3B), EGF (50 ng/ml) and insulin (10 nM) stimulated endogenous AKR1B10 expression and promoter activity. In the AKR1B10 promoter, a putative AP-1 element was found at bp -222 to -212. Deletion or mutation of this AP-1 element abrogated the basal promoter activity and response to EGF and AP-1 proteins. This AP-1 element bound to nuclear proteins extracted from HepG2 cells, and this binding was stimulated by EGF and insulin in a dose-dependent manner. Chromatin immunoprecipitation showed that the AP-1 proteins c-Fos and c-Jun were the predominant factors bound to the AP-1 consensus sequence, followed by JunD and then JunB. The same order was followed in the stimulation of endogenous AKR1B10 expression by AP-1 proteins. Furthermore, c-Fos shRNA (short hairpin RNA) and AP-1 inhibitors/antagonists (U0126 and Tanshinone IIA) inhibited endogenous AKR1B10 expression and promoter activity in HepG2 cells cultured in vitro or inoculated subcutaneously in nude mice. U0126 also inhibited AKR1B10 expression induced by EGF. Taken together, these results suggest that AKR1B10 is up-regulated by EGF and insulin through AP-1 mitogenic signalling and may be implicated in hepatocarcinogenesis.

p38ß, A novel regulatory target of Pokemon in hepatic cells.

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. p38ß, 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 p38ß protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38ß is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells.

Chemical genetics of acetyl-CoA carboxylases.

Chemical genetic studies on acetyl-CoA carboxylases (ACCs), rate-limiting enzymes in long chain fatty acid biosynthesis, have greatly advanced the understanding of their biochemistry and molecular biology and promoted the use of ACCs as targets for herbicides in agriculture and for development of drugs for diabetes, obesity and cancers. In mammals, ACCs have both biotin carboxylase (BC) and carboxyltransferase (CT) activity, catalyzing carboxylation of acetyl-CoA to malonyl-CoA. Several classes of small chemicals modulate ACC activity, including cellular metabolites, natural compounds, and chemically synthesized products. This article reviews chemical genetic studies of ACCs and the use of ACCs for targeted therapy of cancers.

Impact of cytotoxic chemotherapy on aldo-keto reductase family 1 member B10 expression.

OBJECTIVE: Aldo-keto reductase family 1 member B10 (AKR1B10) is a protein that is produced and secreted by a significant number of breast cancers. However, a potential confounder to the use of AKR1B10 as a tumor marker is its elevation in patients given cytotoxic chemotherapy. We therefore conducted a prospective study to analyze AKR1B10 levels in patients with breast cancer receiving neoadjuvant cytotoxic chemotherapy. METHODS: The study enrolled 10 patients from November 2015 to July 2017. All patients had locally advanced, but non-metastatic, breast cancer, and they received neoadjuvant chemotherapy followed by surgery. Serum AKR1B10 levels and tumor imaging were assessed before, during, and after chemotherapy. RESULTS: No increase in serum AKR1B10 levels was noted in patients receiving chemotherapy whose levels were elevated at diagnosis. CONCLUSION: The findings are complex, but the overall data suggest that AKR1B10 is suitable as a tumor marker in patients with elevated levels at the time of diagnosis.