Design of Murine Double Minute 2 Proteolysis Targeting Chimera Degraders with a Built-In Tumor-Targeting Ability.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules to induce the proteasomal degradation of target proteins. Currently, there are no tumor-targeting PROTACs for modulating oncogenic murine double minute 2 (MDM2). AS1411 is a tumor-targeting aptamer that specifically recognizes nucleolin (NCL) overexpressed on the surface of tumor cells. We recently repurposed AS1411 as an MDM2 recruiter since it could form an NCL-bridged ternary complex with MDM2. In this study, we design a PROTAC molecule AS1411-VH032 via conjugating AS1411 with a recruiter of von Hippel-Lindau (VHL) ligase VH032. AS1411-VH032 facilitates tumor-selective degradation of MDM2, leading to tumor shrinkage with no detectable toxicity. Besides being a molecular target, MDM2 also serves as an E3 ligase harnessed by PROTACs. Thus, we developed an AS1411-based homo-PROTAC homoAS1411, which induces tumor-specific suicide degradation of MDM2 and prevents tumor progression without causing side effects. Both AS1411-VH032 and homoAS1411 are promising MDM2 degraders with built-in tumor-targeting ability, which balances the antitumor efficacy with a favorable safety profile.

Thermo-Convective Solution Growth of Vertically Aligned Zinc Oxide Nanowire Arrays for Piezoelectric Energy Harvesting.

The search for a synthesis method to create longer ZnO NWAs with high-quality vertical alignment, and the investigation of their electrical properties, have become increasingly important. In this study, a hydrothermal method for growing vertically aligned arrays of ZnO nanowires (NWs) using localized heating was utilized. To produce longer NWs, the temperature environment of the growth system was optimized with a novel reaction container that provided improved thermal insulation. At a process temperature above ~90 °C, ZnO NWs reached a length of ~26.8 µm within 24 h, corresponding to a growth rate of 1.1 µm/h, nearly double the rate of 0.6 µm/h observed in traditional chemical bath growth using a glass reactor. The densely grown NWs (~1.9/µm2), with a diameter of ~0.65 µm, exhibited a preferred hexagonal c-axis orientation and were vertically aligned to the (100) silicon (Si) substrate. These NW structures have multiple applications, e.g., in piezotronic strain sensors, gas sensing, and piezoelectric energy harvesting. As proof of concept, a piezoelectric nanogenerator (PENG) was fabricated by embedding the NWs in an S1818 polymer matrix over a 15 mm × 15 mm area. Under repeated impulse-type compressive forces of 0.9 N, a maximum peak output voltage of ~95.9 mV was recorded, which is higher by a factor of four to five than the peak output voltage of 21.6 mV previously obtained with NWs measuring ~1.8 µm in length.

Microbial production of 5-epi-jinkoheremol, a plant-derived antifungal sesquiterpene.

Synthetic biology using microbial chassis is emerging as a powerful tool for the production of natural chemicals. In the present study, we constructed a microbial platform for the high-level production of a sesquiterpene from Catharanthus roseus, 5-epi-jinkoheremol, which exhibits strong fungicidal activity. First, the mevalonate and sterol biosynthesis pathways were optimized in engineered yeast to increase the metabolic flux toward the biosynthesis of the precursor farnesyl pyrophosphate. Then, the transcription factor Hac1- and m6A writer Ime4-based metabolic engineering strategies were implemented in yeast to increase 5-epi-jinkoheremol production further. Next, protein engineering was performed to improve the catalytic activity and enhance the stability of the 5-epi-jinkoheremol synthase TPS18, resulting in the variant TPS18I21P/T414S, with the most improved properties. Finally, the titer of 5-epi-jinkoheremol was elevated to 875.25 mg/L in a carbon source-optimized medium in shake flask cultivation. To the best of our knowledge, this is the first study to construct an efficient microbial cell factory for the sustainable production of this antifungal sesquiterpene.IMPORTANCEBiofungicides represent a new and sustainable tool for the control of crop fungal diseases. However, hindered by the high cost of biofungicide production, their use is not as popular as expected. Synthetic biology using microbial chassis is emerging as a powerful tool for the production of natural chemicals. We previously identified a promising sesquiterpenoid biofungicide, 5-epi-jinkoheremol. Here, we constructed a microbial platform for the high-level production of this chemical. The metabolic engineering of the terpene biosynthetic pathway was firstly employed to increase the metabolic flux toward 5-epi-jinkoheremol production. However, the limited catalytic activity of the key enzyme, TPS18, restricted the further yield of 5-epi-jinkoheremol. By using protein engineering, we improved its catalytic efficiency, and combined with the optimization of regulation factors, the highest production of 5-epi-jinkoheremol was achieved. Our work was useful for the larger-scale efficient production of this antifungal sesquiterpene.

Bombinin-BO1 induces hepatocellular carcinoma cell-cycle arrest and apoptosis via the HSP90A-Cdc37-CDK1 axis.

Bombinin-BO1 (BO1), a bombinin peptide derived from the skin secretion of Bombina orientalis, exhibits broad-spectrum antimicrobial activity. To date, the anticancer effect of BO1 remains unclear. This study confirmed cytotoxicity of BO1 on hepatocellular carcinoma cells by inducing S-phase cycle block and apoptosis. In addition, BO1 was found to be localized in cytoplasm through endocytosis. The combined results of pull down, mass spectrometry, and co-immunoprecipitation suggested that BO1 induced misfolding of CDK1 and degradation by competitively binding HSP90A with Cdc37. It was verified that overexpression of HSP90A in BO1-treated cells significantly inhibited degradation of CDK1. In vivo, BO1 inhibited tumor without being toxic to individuals. This study reveals the anti-tumor mechanism of BO1 in inducing cell-cycle arrest and apoptosis by interfering with HSP90A-Cdc37-CDK1 system. This is the first study to analyze the mechanism of BO1 regulation of tumor cells, providing theoretical basis for BO1 treatment of hepatocellular carcinoma.

The inverse associations of glycine and histidine in diet with hyperlipidemia and hypertension.

BACKGROUND: Amino acids are crucial for nutrition and metabolism, regulating metabolic pathways and activities vital to organismal health and stability. Glycine and histidine act as potent antioxidants and anti-inflammatory agents; however, limited knowledge exists regarding the associations between these amino acids and hyperlipidemia and hypertension. The purpose of this study is to investigate the relationship between dietary glycine and histidine, and hyperlipidemia and hypertension. METHODS: This population-based cross-sectional study evaluated the influence of dietary glycine and histidine, as well as their combined effect, on hyperlipidemia and hypertension in Chinese adults participating in the Nutrition Health Atlas Project (NHAP). General characteristics were acquired using a verified Internet-based Dietary Questionnaire for the Chinese. Binary logistic regression, along with gender, age groups, and median energy intake subgroup analyses, was employed to investigate the associations between dietary glycine and histidine and hyperlipidemia and hypertension. A sensitivity analysis was conducted to assess the impact of excluding individuals who smoke and consume alcohol on the results. RESULTS: Based on the study's findings, 418 out of 1091 cases had hyperlipidemia, whereas 673 had hypertension. A significant inverse relationship was found between dietary glycine, histidine, and glycine + histidine and hyperlipidemia and hypertension. Compared with the 1st and 2nd tertiles, the multivariable-adjusted odd ratios (ORs) (95% confidence intervals) (CIs) of the 3rd tertile of dietary glycine for hyperlipidemia and hypertension were 0.64 (0.49-0.84) (p < 0.01) and 0.70 (0.56-0.88) (p < 0.001); histidine was 0.63 (0.49-0.82) (p < 0.01) and 0.80 (0.64-0.99) (p < 0.01); and glycine + histidine was 0.64 (0.49-0.83) (p < 0.01) and 0.74 (0.59-0.92) (p < 0.001), respectively. High glycine and high histidine (HGHH) intake were negatively associated with hyperlipidemia and hypertension OR (95% CIs) were: 0.71 (0.58-0.88) (p < 0.01) and 0.73 (0.61-0.87) (p < 0.01), respectively. CONCLUSIONS: Dietary glycine and histidine, as well as their HGHH group, revealed an inverse relationship with hyperlipidemia and hypertension. Further investigations are needed to validate these findings.

Modulating tumor-associated macrophage polarization by anti-maRCO mAb exerts anti-osteosarcoma effects through regulating osteosarcoma cell proliferation, migration and apoptosis.

PURPOSE: Osteosarcoma is a primary bone tumor lacking optimal clinical treatment options. Tumor-associated macrophages in the tumor microenvironment are closely associated with tumor development and metastasis. Studies have identified the macrophage receptor with collagenous structure (MARCO) as a specific receptor expressed in macrophages. This study aimed to investigate whether anti-MARCO mAb treatment can induce macrophage polarization in the tumor microenvironment and elicit anti-tumor effects. METHODS: THP-1 cells were treated with 20 ng/mL phorbol 12-myristate 13-acetate and 80 ng/mL interleukin-4 for 48 h to induce macrophage polarization to alternatively activated macrophages (M2). Enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, flow cytometry, and bioinformatic analyses were performed to evaluate macrophage polarization. The co-culture groups included a blank group, an M2 macrophage and U2OS co-culture group, and an anti-MARCO mAb-treated M2 macrophage group. Cell viability assays, cell scratch tests, apoptosis, and cell cycle analyses were performed to determine the effects of anti-MARCO mAb-treated macrophages on osteosarcoma cells. RESULTS: It was demonstrated that anti-MARCO mAb can drive macrophages toward classically activated macrophage (M1) polarization. Anti-MARCO mAb promoted the secretion of pro-inflammatory factors by macrophages, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta, interleukin-6 and interleukin-23. Studies on in vitro co-culture models have revealed that macrophages treated with anti-MARCO mAb can suppress the growth and migration of osteosarcoma cells, induce cell apoptosis, and inhibit cell cycle progression of osteosarcoma cells through M1 polarization of macrophages in vitro. CONCLUSION: Anti-MARCO mAb treatment exerts anti-osteosarcoma effects by affecting macrophage polarization toward M1 macrophages, offering a potential new therapeutic approach for treating osteosarcoma.

Synergistic role of phenylpropanoid biosynthesis and citrate cycle pathways in heavy metal detoxification through secretion of organic acids.

Excessive heavy metal contaminants in soils have serious ecological and environmental impacts, and affect plant growth and crop yields. Phytoremediation is an environmentally friendly means of lowering heavy metal concentrations in soils. In this study, we analyzed phenotypic and physiological traits, and the transcriptome and metabolome, of sheepgrass (Leymus chinensis) exposed to cadmium (Cd), lead (Pb), or zinc (Zn). Phenotypic and physiological analysis indicated that sheepgrass had strong tolerance to Cd/Pb/Zn. Transcriptomic analysis revealed that phenylpropanoid biosynthesis and organic acid metabolism were enriched among differentially expressed genes, and metabolomic analysis indicated that the citrate cycle was enriched in response to Cd/Pb/Zn exposure. Genes encoding enzymes involved in the phenylpropanoid and citrate cycle pathways were up-regulated under the Cd/Pb/Zn treatments. Organic acids significantly reduced heavy metal accumulation and improved sheepgrass tolerance of heavy metals. The results suggest that synergistic interaction of the phenylpropanoid and citrate cycle pathways in sheepgrass roots induced organic acid secretion to alleviate heavy metal toxicity. A cascade of enzymes involved in the interacting pathways could be targeted in molecular design breeding to enhance phytoremediation.

Silencing of tropomodulin 1 inhibits acute myeloid leukemia cell proliferation and tumor growth by elevating karyopherin alpha 2-mediated autophagy.

Evidence shows that tropomodulin 1 (TMOD1) is a powerful diagnostic marker in the progression of several cancer types. However, the regulatory mechanism of TMOD1 in tumor progression is still unclear. Here, we showed that TMOD1 was highly expressed in acute myeloid leukemia (AML) specimens, and TMOD1-silencing inhibited cell proliferation by inducing autophagy in AML THP-1 and MOLM-13 cells. Mechanistically, the C-terminal region of TMOD1 directly bound to KPNA2, and TMOD1-overexpression promoted KPNA2 ubiquitylation and reduced KPNA2 levels. In contrast, TMOD1-silencing increased KPNA2 levels and facilitated the nuclear transfer of KPNA2, then subsequently induced autophagy and inhibited cell proliferation by increasing the nucleocytoplasmic transport of p53 and AMPK activation. KPNA2/p53 inhibitors attenuated autophagy induced by silencing TMOD1 in AML cells. Silencing TMOD1 also inhibited tumor growth by elevating KPNA2-mediated autophagy in nude mice bearing MOLM-13 xenografts. Collectively, our data demonstrated that TMOD1 could be a novel therapeutic target for AML treatment.

Research on drug treatment and the novel signaling pathway of chronic atrophic gastritis.

BACKGROUND: Chronic atrophic gastritis (CAG) is a global digestive system disease and one of the important causes of gastric cancer. The incidence of CAG has been increasing yearly worldwide. PURPOSE: This article reviews the latest research on the common causes and future therapeutic targets of CAG as well as the pharmacological effects of corresponding clinical drugs. We provide a detailed theoretical basis for further research on possible methods for the treatment of CAG and reversal of the CAG process. RESULTS: CAG often develops from chronic gastritis, and its main pathological manifestation is atrophy of the gastric mucosa, which can develop into gastric cancer. The drug treatment of CAG can be divided into agents that regulate gastric acid secretion, eradicate Helicobacter. pylori (H. pylori), protect gastric mucous membrane, or inhibit inflammatory factors according to their mechanism of action. Although there are limited specific drugs for the treatment of CAG, progress is being made in defining the pathogenesis and therapeutic targets of the disease. Growing evidence shows that NF-κB, PI3K/AKT, Wnt/ ß-catenin, MAPK, Toll-like receptors (TLRs), Hedgehog, and VEGF signaling pathways play an important role in the development of CAG.

The microbial biosynthesis of noncanonical terpenoids.

Terpenoids are a class of structurally complex, naturally occurring compounds found predominantly in plant, animal, and microorganism secondary metabolites. Classical terpenoids typically have carbon atoms in multiples of five and follow well-defined carbon skeletons, whereas noncanonical terpenoids deviate from these patterns. These noncanonical terpenoids often result from the methyltransferase-catalyzed methylation modification of substrate units, leading to irregular carbon skeletons. In this comprehensive review, various activities and applications of these noncanonical terpenes have been summarized. Importantly, the review delves into the biosynthetic pathways of noncanonical terpenes, including those with C6, C7, C11, C12, and C16 carbon skeletons, in bacteria and fungi host. It also covers noncanonical triterpenes synthesized from non-squalene substrates and nortriterpenes in Ganoderma lucidum, providing detailed examples to elucidate the intricate biosynthetic processes involved. Finally, the review outlines the potential future applications of noncanonical terpenoids. In conclusion, the insights gathered from this review provide a reference for understanding the biosynthesis of these noncanonical terpenes and pave the way for the discovery of additional unique and novel noncanonical terpenes. KEY POINTS: •The activities and applications of noncanonical terpenoids are introduced. •The noncanonical terpenoids with irregular carbon skeletons are presented. •The microbial biosynthesis of noncanonical terpenoids is summarized.

Loureirin A Promotes Cell Differentiation and Suppresses Migration and Invasion of Melanoma Cells via WNT and AKT/mTOR Signaling Pathways.

Resina Draconis is a traditional Chinese medicine, with the in-depth research, its medicinal value in anti-tumor has been revealed. Loureirin A is extracted from Resina Draconis, however, research on the anti-tumor efficacy of Loureirin A is rare. Herein, we investigated the function of Loureirin A in melanoma. Our research demonstrated that Loureirin A inhibited the proliferation of and caused G0/G1 cell cycle arrest in melanoma cells in a concentration-dependent manner. Further study showed that the melanin content and tyrosinase activity was enhanced after Loureirin A treatment, demonstrated that Loureirin A promoted melanoma cell differentiation, which was accompanied with the reduce of WNT signaling pathway. Meanwhile, we found that Loureirin A suppressed the migration and invasion of melanoma cells through the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Taken together, this study demonstrated for the first time the anti-tumor effects of Loureirin A in melanoma cells, which provided a novel therapeutic strategy against melanoma.

A novel polysaccharide isolated from Coriolus versicolor polarizes M2 macrophages into an M1 phenotype and reversesits immunosuppressive effect on tumor microenvironment.

Converting M2 macrophages into an M1 phenotype in the tumor microenvironment, provides a new direction for tumor treatment. Here, we further report CVPW-1, a new polysaccharide of 1.03 × 106 Da that was isolated from Coriolus versicolor. Its monosaccharide was composed of mannose, glucose, and galactose at a ratio of 1.00:8.73:1.68. The backbone of CVPW-1 was composed of (1 â†’ 3)-linked α-D-Glcp residues and (1 â†’ 3,6)-linked α-D-Glcp residues that branched at O-6. The branch consisted of (1 â†’ 6)-linked α-D-Glcp residues and (1 â†’ 4)-linked α-D-Glap, and some branches were terminated with (1→)-linked ß-D-Manp residues according to the results of HPLC, FT-IR, GC-MS, 1D and 2D NMR. Meanwhile, CVPW-1 could polarize M2 macrophages to M1 phenotypein vitro by binding to TLR4 and inducing the activation of Akt, JNK and NF-κB. This process involved reversing the functional inhibition of CD8+ T lymphocytes by inhibiting the expression of TREM2 in M2 macrophages. The in vivo experiments showed that oral administration of CVPW-1 could inhibit the growth of tumor in mice and polarize TAMs to M1 phenotype. Thus, the novel polysaccharide CVPW-1 from Coriolus versicolor might activate a variety of immune cells and then play an anti-tumor role. These results demonstrated that CVPW-1 could be developed as a potential immuno-oncology treatment reagent.

Farrerol suppresses osteoclast differentiation and postmenopausal osteoporosis by inhibiting the nuclear factor kappa B signaling pathway.

Excessive bone resorption caused by upregulated osteoclast activity is a key factor in osteoporosis pathogenesis. Farrerol is a typical natural flavanone and exhibits various pharmacological actions. However, the role and mechanism of action of farrerol in osteoclast differentiation regulation remain unclear. This study aimed to evaluate the effects and mechanism of farrerol on the inhibition of osteoclastogenesis. Tartrate-resistant acid phosphatase staining, F-actin staining, and the pit formation assay were performed to examine the differentiation and functions of osteoclasts in vitro. The expression of proteins associated with the nuclear factor kappa B and mitogen-activated protein kinase signaling pathways was analyzed by western blotting. Dual X-ray absorptiometry, microcomputed tomography, and histopathological and immunohistochemical analyses were performed to determine the therapeutic effect of farrerol in vivo bone loss prevention. The effects of farrerol on osteoblastic bone formation were assessed using alkaline phosphatase, alizarin red S staining, and calcein-alizarin red S double labeling. Farrerol inhibited osteoclastogenesis and bone resorption in osteoclasts by suppressing nuclear factor kappa B signaling rather than mitogen-activated protein kinase signaling in vitro. Farrerol protected mice against ovariectomy-induced bone loss by inhibiting osteoclast-mediated bone resorption, instead of promoting osteoblast-mediated bone formation in vivo. The findings of the current study revealed that farrerol is a potential therapeutic agent for osteoporosis.

Metal-Free 1,3-Boronate Rearrangement to Ketones Driven by Visible Light.

Boronate rearrangements, such as the Matteson and Petasis reactions, are valuable metal-free reactions for the transfer of the carbo group on boron to intramolecular electrophilic sites. However, only highly reactive electrophiles are suitable, and ketones are too inactive for those boronate rearrangements due to the high energy barriers. We disclose here the 1,3-boronate rearrangement to ketones, for which a high energy barrier (44.9 kcal/mol) is prohibitory for thermal reactions in the ground state. The reaction is enabled by the key keto-enol-boronate bidentate complex formation in situ, which absorbs visible light to reach the excited state for the chemoselective 1,3-boronate rearrangement to ketones. Experimental and computational investigations exclude free radical intermediates from organoboronates. The aryl, alkenyl, and alkyl boronic acids react with various 1,3-diketones driven by visible light irradiation to construct structurally diverse ß-keto tertiary alcohols under metal-free conditions. The reaction demonstrates substrate diversity with 58 examples, yields up to 98 %, and it is suitable for gram-scale synthesis.

Novel sulfonyl-substituted tetrandrine derivatives for colon cancer treatment by inducing mitochondrial apoptosis and inhibiting PI3K/AKT/mTOR pathway.

Tetrandrine (TET) possesses multiple pharmacological activities and could suppress tumor proliferation via PI3K pathway inhibition. However, inferior antitumor activity and potential toxicity limit its clinical application. In the present study, a series of 14-sulfonamide and sulfonate TET derivatives were designed, synthesized, and evaluated for biological activities. Through structural-activity relationship studies, compound 3c with α, ß-unsaturated carbonyl group exhibited the most potent activity against all tested tumor cell lines (including Hela, HCT116, HepG2, MCF-7, and SHSY5Y), as well as negligible toxicity against normal cell lines LO2 and HEK293. Additionally, compound 3c effectively inhibited HCT116 and CT26 cell proliferation in vitro with increased cell proportion in the G2/M phase, activated the mitochondrial apoptosis pathway, and induced colon cancer cell apoptosis by suppressing the PI3K/AKT/mTOR pathway. The further molecular docking results confirmed that compound 3c is potentially bound to multiple residues in PI3K with a stronger binding affinity than TET. Ultimately, compound 3c dramatically suppressed tumor growth in the CT26 xenograft tumor model, without noticeable visceral toxicity detected in the high-dose group. In summary, compound 3c might present new insights for designing new PI3K inhibitors and be a potential candidate for colon cancer treatment.

Influence of Nitrogen Supply on Growth, Antioxidant Capacity and Cadmium Absorption of Kenaf (Hibiscus cannabinus L.) Seedlings.

Kenaf (Hibiscus cannabinus L.) is considered suitable for the remediation of cadmium (Cd)-contaminated farmlands, because of its large biomass and resistance to Cd stress. The addition of nitrogen (N) fertilizer is an important measure used to increase crop yields, and it may also affect Cd accumulation in plants. To clarify the effects of different forms and concentrations of N on plant growth and Cd absorption in kenaf, a hydroponic experiment was conducted using three N forms (NH4+-N, NO3--N and urea-N) at four concentrations (0, 2, 4 and 8 mM, 0 mM as control) under Cd stress (30 µM). The plant growth, the antioxidant enzyme activity and the Cd contents of various parts of the kenaf seedlings were measured. The results showed that the N form had the greatest impact on the growth of the kenaf and the absorption and transport of the Cd, followed by the interaction effect between the N type and the concentration. Compared to the control, the addition of N fertilizer promoted the growth of kenaf to varying degrees. Among all the treatments, the use of 2 mM of NO3--N enhanced the biomass and Cd accumulation to the greatest extent compared to CK from 2.02 g to 4.35 g and 341.30 µg to 809.22 µg per plant, respectively. The NH4+-N significantly reduced the Cd contents of different parts but enhanced the translocation factors of Cd stem to root (TF S/R) and leaf to stem (TF L/S) by 34.29~78.57% and 45.10~72.55%, respectively. The peroxidase (POD), superoxide dismutase (SOD) and catalase (CAT) enzyme activities of the kenaf increased with the N treatments, especially with NH4+-N. Overall, applying low concentrations of NO3--N can better promote the extraction of Cd by kenaf.

Progress of research into the pharmacological effect and clinical application of the traditional Chinese medicine Rehmanniae Radix.

The traditional Chinese medicine (TCM) Rehmanniae Radix (RR) refers to the fresh or dried root tuber of the plant Rehmannia glutinosa Libosch of the family Scrophulariaceae. As a traditional Chinese herbal medicine (CHM), it possesses multiple effects, including analgesia, sedation, anti-inflammation, antioxidation, anti-tumor, immunomodulation, cardiovascular and cerebrovascular regulation, and nerve damage repair, and it has been widely used in clinical practice. In recent years, scientists have extensively studied the active components and pharmacological effects of RR. Active ingredients mainly include iridoid glycosides (such as catalpol and aucuboside), phenylpropanoid glycosides (such as acteoside), other saccharides, and unsaturated fatty acids. In addition, the Chinese patent medicine (CPM) and Chinese decoction related to RR have also become major research subjects for TCM practitioners; one example is the Bolus of Six Drugs, which includes Rehmannia, Lily Bulb and Rehmannia Decoction, and Siwu Decoction. This article reviews recent literature on RR; summarizes the studies on its chemical constituents, pharmacological effects, and clinical applications; and analyzes the progress and limitations of current investigations to provide reference for further exploration and development of RR.

Complex roles of Hippo-YAP/TAZ signaling in hepatocellular carcinoma.

BACKGROUND: The Hippo signaling pathway is an evolutionarily conserved signaling module that controls organ size in different species, and the disorder of the Hippo pathway can induce liver cancer in organisms, especially hepatocellular carcinoma (HCC). The exact mechanism that causes cancer is still unknown. Recent studies have shown that it is a classical kinase cascade that phosphorylates the Mst1/2-sav1 complex and activates the phosphorylation of the Lats1/2-mob1A/B complex for inactivating Yap and Taz. These kinases and scaffolds are regarded as primary regulators of the Hippo pathway, and help in activating a variety of carcinogenic processes. Among them, Yap/Taz is seen to be the main effector molecule, which is downstream of the Hippo pathway, and its abnormal activation is related to a variety of human cancers including liver cancer. Currently, since Yap/Taz plays a variety of roles in cancer promotion and tumor regeneration, the Hippo pathway has emerged as an attractive target in recent drug development research. METHODS: We collect and review relevant literature in web of Science and Pubmed. CONCLUSION: This review highlights the important roles of Yap/Taz in activating Hippo pathway in liver cancer. The recent findings on the crosstalks between the Hippo and other cancer associated pathways and moleculars are also discussed. In this review, we summarized and discussed recent breakthroughs in our understanding of how key components of the Hippo-YAP/TAZ pathway influence the hepatocellular carcinoma, including their effects on tumor occurrence and development, their roles in regulating metastasis, and their function in chemotherapy resistance. Further, the molecular mechanism and roles in regulating cross talk between Hippo-YAP/TAZ pathway and other cancer-associated pathways or oncogenes/cancer suppressor genes were summarized and discussed. More, many other inducers and inhibitors of this signaling cascade and available experimental therapies against the YAP/TAZ/TEAD axis were discussed. Targeting this pathway for cancer therapy may have great significance in the treatment of hepatocellular carcinoma. Graphical summary of the complex role of Hippo-YAP/TAZ signaling in hepatocellular carcinoma.

Targeting HSP90 with picropodophyllin suppresses gastric cancer tumorigenesis by disrupting the association of HSP90 and AKT.

Gastric cancer (GC) is one of the most common malignant tumors worldwide. Thus, the development of safe and effective therapeutic compounds for GC treatment is urgently required. Here, we aimed to examine the role of picropodophyllin (PPP), a compound extracted from the rhizome of Dysosma versipellis (Hance) M. Cheng ex Ying, on the proliferation of GC cells. Our study revealed that PPP inhibits the proliferation of GC cells in a dose-dependent manner by inducing apoptosis. Moreover, our study elucidated that PPP suppresses the growth of GC tumor xenografts with no side effects of observable toxicity. Mechanistically, PPP exerts its effects by blocking the AKT/mammalian target of rapamycin (mTOR) signaling pathway; these effects are markedly abrogated by the overexpression of constitutively active AKT. Furthermore, drug affinity responsive target stability (DARTS) and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) revealed that heat shock protein 90 (HSP90) may be a potential target of PPP. Surface plasmon resonance and immunoprecipitation assay validated that PPP directly targets HSP90 and disrupts the binding of HSP90 to AKT, thereby suppressing GC cell proliferation. Thus, our study revealed that PPP may be a promising therapeutic compound for GC treatment.