Emerging Roles of SPT5 in Transcription.

Suppressor of Ty homolog-5 (SPT5) discovered in the yeast mutant screens as a suppressor of mutation caused by the insertion of the Transposons of yeast (Ty) element along with SPT4, with which it forms a holoenzyme complex known as DRB sensitivity-inducing factor (DSIF) and plays an essential role in the regulation of transcription. SPT5 is a highly conserved protein across all three domains of life and performs critical functions in transcription, starting from promoter-proximal pausing to termination. We also highlight the emerging role of SPT5 in other non-canonical functions, such as the regulation of post-translational modifications (PTM) and the transcriptional regulation of non-coding genes. Also, in brief, we highlight the clinical implications of SPT5 dysregulation.

Non-POU Domain-Containing Octomer-Binding (NONO) protein expression and stability promotes the tumorigenicity and activation of Akt/MAPK/ß-catenin pathways in human breast cancer cells.

Breast cancer is one of the most common cancers with a high mortality rate, underscoring the need to identify new therapeutic targets. Here we report that non-POU domain-containing octamer-binding (NONO) protein is overexpressed in breast cancer and validated the interaction of the WW domain of PIN1 with c-terminal threonine-proline (thr-pro) motifs of NONO. The interaction of NONO with PIN1 increases the stability of NONO by inhibiting its proteasomal degradation, and this identifies PIN1 as a positive regulator of NONO in promoting breast tumor development. Functionally, silencing of NONO inhibits the growth, survival, migration, invasion, epithelial to mesenchymal transition (EMT), and stemness of breast cancer cells in vitro. A human metastatic breast cancer cell xenograft was established in transparent zebrafish (Danio rerio) embryos to study the metastatic inability of NONO-silenced breast cancer cells in vivo. Mechanistically, NONO depletion promotes the expression of the PDL1 cell-surface protein in breast cancer cells. The identification of novel interactions of NONO with c-Jun and ß-catenin proteins and activation of the Akt/MAPK/ß-catenin signaling suggests that NONO is a novel regulator of Akt/MAPK/ß-catenin signaling pathways. Taken together, our results indicated an essential role of NONO in the tumorigenicity of breast cancer and could be a potential target for anti-cancerous drugs. Video Abstract.

Phytochemical Analysis and In Vitro Antioxidant and Antibacterial Activity of Different Solvent Extracts of Beilschmiedia roxburghiana Nees Stem Barks.

Plants have long been considered as a basis of medicines for different indigenous cultures around the globe. They continue as a prominent source of important phytoconstituents which exhibit significant biological activities. In this study, we performed the phytochemical screening, estimation of total phenolic and flavonoids, antioxidants, and antimicrobial activities of the stem bark of Beilschmiedia roxburghiana Nees using different solvents. The total phenolic and total flavonoid contents ranged from 106.73 ± 1.62 mg GAE/g and 99.32 ± 0.66 mg QE/g (methanol extract) to 65.59 ± 1.79 mg GAE/g and 29.98 ± 0.90 mg QE/g (n-hexane extract), respectively. The maximum 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity with a half-maximal inhibitory concentration (IC50) of 39.86 ± 3.69 µg/mL was observed for methanol extract followed by aqueous (IC50 = 43.55 ± 6.16 µg/mL), ethyl acetate (IC50 = 44.30 ± 5.88 µg/mL), dichloromethane (IC50 = 71.50 ± 4.70 µg/mL), and the lowest activity was observed for n-hexane extract. The disc diffusion method revealed that the ethyl acetate extract exhibited relatively higher activity against Salmonella typhi (ZOI = 13 mm), and moderate activities against Shigella sonnei, Acinetobacter baumannii, Klebsiella pneumoniae, and Staphylococcus aureus (ZOI = 12 mm). The methanol and aqueous extracts showed nearly parallel and the n-hexane and dichloromethane extracts exhibited mild antibacterial activities. The results indicated that the polarity index of the extracting solvents amplified the biological activities of the extract. The study is helpful to support the validity of the traditional application of the plant as natural medicine.

Synthesis, biological evaluation, and in silico studies of indole-tethered pyrazoline derivatives as anticancer agents targeting topoisomerase IIα.

We herein report a new series of indole-tethered pyrazoline derivatives as potent anticancer agents. A total of 12 compounds were designed and synthesized by conventional as well as microwave-irradiated synthesis methods. The latter method results in a significant reduction in the duration of reaction along with improved yields. All synthesized derivatives (7a-7l) were evaluated for their cytotoxic activity against A431, HeLa, and MDAMB-231 cell lines. Compounds 7a and 7b were found most potent in the series and demonstrated an IC50 value of 3.17 and 5.16 µM against the A431 cell line, respectively, compared to the standard drug doxorubicin. Compounds 7a and 7b significantly suppress colony formation, migration, and S phase cell cycle arrest of A431 cells. Furthermore, compound 7a regulated the expression of apoptotic proteins causing the downregulation of procaspase 3/9, antiapoptotic protein Bcl-xL, and upregulation of proapoptotic protein Bax in a dose-dependent manner. Topoisomerase enzyme inhibition assay confirmed that compounds 7a and 7b can significantly inhibit topoisomerase IIα. In vivo oral acute toxicity of compounds 7a and 7b revealed that both compounds are safe compared to doxorubicin; cardiomyopathy studies showed normal architecture of cardiomyocytes and myofibrils. In addition, molecular docking studies revealed the possible interaction of compounds 7a and 7b within the active binding site of the topoisomerase enzyme. The 100 ns molecular dynamic simulation of compounds 7a and 7b proved that both compounds validate all screening parameters.

SUPT5H Post-Transcriptional Silencing Modulates PIN1 Expression, Inhibits Tumorigenicity, and Induces Apoptosis of Human Breast Cancer Cells.

BACKGROUND/AIMS: Breast cancer (BrCa) is one of the most common cancers and a highly heterogenous disease, both at the pathological and molecular levels. A common element for the progression of cancer is the presence of aberrant transcription. Targeting the misregulation of transcription may serve as a tool for cancer therapeutics. SUPT5H (Suppressor of Ty 5 homolog) is a highly conserved RNA polymerase II-associated transcription elongation and processivity factor. However, few studies have examined the relationship between SUPT5H and cancer. METHODS: Yeast two-hybrid and colocalization by immunofluorescence were performed to investigate protein-protein interaction. Colony formation assay, CTG assay, and crystal violet assays were performed for cell viability, clonogenicity, and cell proliferation study. Data mining was performed for expression analysis of SUPT5H in breast cancers. Flow cytometry was performed for the assessment of cell cycle and apoptosis. The Transwell chambers were employed for the migration and invasion assays. Quantitative real-time polymerase chain reaction (qRT PCR) and Western blotting were performed to measure the mRNA and protein levels of SUPT5H and other markers related to viability, migration, cell cycle, and apoptosis. Silent mutations were generated for rescue experiments. The biological function of SUPT5H was investigated through siRNA depletion of SUPT5H mRNA in vitro. RESULTS: We showed that SUPT5H is upregulated in breast cancer tissue as compared with the adjacent normal tissue in breast cancer patients. In human breast cancer cells, the levels of SUPT5H and PIN1 are positively correlated with each other. Our biochemical analysis showed that PIN1 interacts with SUPT5H through WW domain, that was required to promote SUPT5H protein stability. Depletion of SUPT5H by siRNA technology reduced the tumorigenic and metastatic properties, promoted s-phase cell cycle arrest and apoptosis of MDA-MB-231 cells. Moreover, depletion of SUPT5H abrogated MAPK molecules thereby regulates the oncogenic behavior of breast cancer cells. CONCLUSION: Our findings demonstrated an essential role of SUPT5H in BrCa tumorigenicity by regulating the expression levels of genes that control proliferation, migration, cell cycle, and apoptosis of breast cancer MDA-MB-231 cells.

Design and synthesis of newer 1,3,4-oxadiazole and 1,2,4-triazole based Topsentin analogues as anti-proliferative agent targeting tubulin.

A set of two series of 1,3,4-oxadiazole (11a-n) and 1,2,4-Triazole (12a, c, e, g, h, j-n) based topsentin analogues were prepared by replacing imizadole moiety of topsentin through a multistep synthesis starting from indole. All the compounds synthesized were submitted for single dose (10 µM) screening against a NCI panel of 60-human cancer cell lines. Among all cancer cell lines, colon (HCC-2998) and Breast (MCF-7, T-47D) cancer cell lines were found to be more susceptible for this class of compounds. Among the compounds tested, compounds 11a, 11d, 11f, 12e and 12h, were exhibited good anti-proliferative activity against various cancer cell lines. Compounds 11d, 12e and 12h demonstrated better activity with IC50 2.42 µM, 3.06 µM, and 3.30 µM respectively against MCF-7 human cancer cell line than that of the standard drug doxorubicin IC50 6.31 µM. Furthermore, 11d induced cell cycle arrest at G0/G1 phase and also disrupted mitochondrial membrane potential with reducing cell migration potential of MCF-7 cells in dose dependent manner. In vitro microtubule polymerization assays found that compound 11d disrupt tubulin dynamics by inhibiting tubulin polymerization with IC50 3.89 µM compared with standard nocodazole (IC50 2.49 µM). In silico docking studies represented that 11d was binding at colchicine binding site of ß-tubulin. Compound 11d emerged as lead molecule from the library of compounds tested and this may serve as a template for further drug discovery.

Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein-Protein Interaction Data.

High content protein interaction screens have revolutionized our understanding of protein complex assembly. However, one of the major challenges in translation of high content protein interaction data is identification of those interactions that are functionally relevant for a particular biological question. To address this challenge, we developed a relevance ranking platform (RRP), which consist of modular functional and bioinformatic filters to provide relevance rank among the interactome proteins. We demonstrate the versatility of RRP to enable a systematic prioritization of the most relevant interaction partners from high content data, highlighted by the analysis of cancer relevant protein interactions for oncoproteins Pin1 and PME-1. We validated the importance of selected interactions by demonstration of PTOV1 and CSKN2B as novel regulators of Pin1 target c-Jun phosphorylation and reveal previously unknown interacting proteins that may mediate PME-1 effects via PP2A-inhibition. The RRP framework is modular and can be modified to answer versatile research problems depending on the nature of the biological question under study. Based on comparison of RRP to other existing filtering tools, the presented data indicate that RRP offers added value especially for the analysis of interacting proteins for which there is no sufficient prior knowledge available. Finally, we encourage the use of RRP in combination with either SAINT or CRAPome computational tools for selecting the candidate interactors that fulfill the both important requirements, functional relevance, and high confidence interaction detection.

Correction to 1,2,3-Triazole Tethered Hybrid Capsaicinoids as Antiproliferative Agents Active against Lung Cancer Cells (A549).

[This corrects the article DOI: 10.1021/acsomega.2c03325.].

Membrane linked RNA glycosylation as new trend to envision epi-transcriptome epoch.

RNAs play several prominent roles in the cellular environment ranging from structural, messengers, translators, and effector molecules. RNA molecules while performing these roles are associated with several chemical modifications occurring post-transcriptionally, responsible for these supporting vital functions. The recent documentation of surface RNA modification with sialic acid residues has sparked advancement to the framework of RNA modifications. Glycan modification of surface RNA which was previously known to modify only proteins and lipids has opened new vistas to explore how these surface RNA modifications affect the cellular responses and phenotype. This paradigm shift in RNA biology with a vision of "glycans being all over the cells" has posed the field with a repertoire of questions and has given headway to the RNA world hypothesis. The review provides a comprehensive overview of glycoRNA discovery with a conceptual understanding of its previous underlying discoveries and their biological consequences with possible insights into the dynamic influence of this modification on their molecular versatility deciding cancer-immunology fate with potential implications of these glycosylation in cellular interaction, signaling, immune regulation, cancer evasion and proliferation.

5-Methoxyisatin N(4)-Pyrrolidinyl Thiosemicarbazone (MeOIstPyrd) Restores Mutant p53 and Inhibits the Growth of Skin Cancer Cells, In Vitro.

A series of novel thiosemicarbazone derivatives containing 5-methoxy isatin were designed and synthesized with modification on N(4) position. Derivatives considering structure-activity relationship have been designed and synthesized by condensing thiosemicarbazide with 5-methoxy isatin. The synthesized compounds were characterized by elemental analysis, FT-IR spectroscopy, UV-visible spectroscopy, NMR (1H, 13C) spectroscopy, mass spectrometry, and a single-crystal study. Biological evaluation of the synthesized compounds revealed that MeOIstPyrd is the most promising compound against skin cancer cell line, A431, with an IC50 value of 0.9 µM. In addition, MeOIstPyrd also exhibited low toxicity against the normal human fibroblast and the human embryonic kidney 293 cell line, HLF-1, and HEK293, respectively. Furthermore, the mechanistic study revealed that MeOIstPyrd efficiently inhibited cell proliferation, migration, and spheroid formation by activating the mitochondrial intrinsic apoptotic pathway. MeOIstPyrd also induces DNA damage and activates p53 irrespective of the p53 status. It increases the half-life of p53 and stabilizes p53 by phosphorylating it at ser15. Moreover, MeOIstPyrd was found to bind to MDM2 in the p53 sub-pocket and, therefore, block p53-MDM2 interaction. Our result exhibited potential anticancer activity of MeOIstPyrd in the A431 cell line and its ability in restoring mutant p53, which is an interesting and promising strategy for cancer therapeutics.

PP2A methylesterase PME-1 suppresses anoikis and is associated with therapy relapse of PTEN-deficient prostate cancers.

While organ-confined prostate cancer (PCa) is mostly therapeutically manageable, metastatic progression of PCa remains an unmet clinical challenge. Resistance to anoikis, a form of cell death initiated by cell detachment from the surrounding extracellular matrix, is one of the cellular processes critical for PCa progression towards aggressive disease. Therefore, further understanding of anoikis regulation in PCa might provide therapeutic opportunities. Here, we discover that PCa tumours with concomitant inhibition of two tumour suppressor phosphatases, PP2A and PTEN, are particularly aggressive, having < 50% 5-year secondary-therapy-free patient survival. Functionally, overexpression of PME-1, a methylesterase for the catalytic PP2A-C subunit, inhibits anoikis in PTEN-deficient PCa cells. In vivo, PME-1 inhibition increased apoptosis in in ovo PCa tumour xenografts, and attenuated PCa cell survival in zebrafish circulation. Molecularly, PME-1-deficient PC3 cells display increased trimethylation at lysines 9 and 27 of histone H3 (H3K9me3 and H3K27me3), a phenotype known to correlate with increased apoptosis sensitivity. In summary, our results demonstrate that PME-1 supports anoikis resistance in PTEN-deficient PCa cells. Clinically, these results identify PME-1 as a candidate biomarker for a subset of particularly aggressive PTEN-deficient PCa.

1,2,3-Triazole Tethered Hybrid Capsaicinoids as Antiproliferative Agents Active against Lung Cancer Cells (A549).

A series of novel 1,2,3-triazole derivatives of capsaicin and its structural isomer (new natural product hybrid capsaicinoid) were synthesized by exploiting one-/two-point modification of capsaicin without altering the amide linkage (neck). The newly synthesized compounds were screened for their antiproliferative activity against an NCI panel of 60 cancer cell lines at a single dose of 10 µM. Most of the compounds have demonstrated reduced growth between 55 and 95%, whereas capsaicin (10) has shown reduced growth between 0 and 24%. Compounds showing more than 50% growth inhibition were further evaluated for the IC50 value. Among the cell lines tested, lung cancer cell lines (A549, NCI-H460) were found to be more susceptible toward most of the synthesized compounds. Compounds 14g and 14j demonstrated good antiproliferative activity in NCI-H460 with IC50 values of 6.65 and 5.55 µM, respectively, while compounds 18b, 18c, 18f, and 18m demonstrated potential antiproliferative activity in A549 cell lines with IC50 values ranging between 2.9 and 10.5 µM. Among the compounds, compound 18f was found to demonstrate the best activity with an IC50 value of 2.91 µM against A549. Furthermore, 18f induces cell cycle arrest at the S-phase and disrupts the mitochondrial membrane potential, reducing cell migration potential by inducing cellular apoptosis and higher ROS generation along with a decrease in mitochondrial membrane potential in addition to surface and nuclear morphological alterations such as a reduction in the number and shrinkage of cells coupled with nuclear blabbing indicating the sign of apoptosis of A549 non-small cell lung cancer cell lines. Compound 18f has emerged as a lead molecule and may serve as a template for further discovery of capsaicinoid scaffolds.

Novel role of Pin1 induction in type II collagen-mediated rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in joints and subsequent destruction of cartilage and bone. Inflammatory mediators such as PGs and proinflammatory cytokines contribute to RA progress. Pin1, a peptidyl prolyl isomerase, plays important pathophysiological roles in several diseases, including cancer and neurodegeneration. We found that both Pin1 and cyclooxygenase-2 (COX-2) were highly expressed in ankle tissues of type II collagen-induced RA mice. HTB-94 cells overexpressing Pin1 and primary cultured human chondrocytes showed increased basal expression of proinflammatory proteins (COX-2, inducible NO synthase, TNF-alpha, and IL-1beta). Site-directed mutagenesis revealed that Pin1-mediated transcriptional activation of COX-2 was coordinately regulated by NF-kappaB, CREB, and C/EBP. Gel shift, reporter gene, and Western blot analyses confirmed that NF-kappaB, CREB, and C/EBP were consistently activated in chondrocytes overexpressing Pin1. Treatment of RA mice with juglone, a chemical inhibitor of Pin1, significantly reduced RA progress and COX-2 expression in the ankle tissues. Moreover, juglone dose dependently decreased the basal COX-2 expression in primary cultured chondrocytes from RA patients. These results demonstrate that Pin1 induction during RA progress stimulates proinflammatory protein expression by activating NF-kappaB, CREB, and C/EBP, and suggest that Pin1 is a potential therapeutic target of RA.

Anticancer Potential of Coumarin and its Derivatives.

Coumarins are found in higher plants like Rutaceae and Umbelliferae and essential oils of cinnamon bark, cassia leaf, and lavender oil. Coumarin compounds show different biological properties, viz antimicrobial, antibacterial, antifungal, antioxidant, antitumor, anti-HIV, antihypertension, anticoagulant, anticancer, antiviral, anti-inflammatory, analgesics, antidiabetic, anti-depressive, and other bioactive properties. Coumarin and its derivatives possess anticancer activity against different types of cancers such as prostate, renal, breast, laryngeal, lung, colon, CNS, leukemia, malignant melanoma. In this review, current developments of coumarin-based anticancer agents viz simple coumarin, furanocoumarin, pyranocoumarin, pyrone-substituted coumarin, and their important derivatives have been discussed. The coumarin-triazole, coumarin-chalcone, coumarin-thiosemicarbazone derivatives, and coumarin-metal complexes have been found more potent than coumarin. Hence, further study and structural improvement on coumarin and its derivatives may lead to the design and development of more potent anticancer agents.

Apoptosis Inducing 1,3,4-Oxadiazole Conjugates of Capsaicin: Their In Vitro Antiproliferative and In Silico Studies.

A series of 1,3,4-oxadiazole tethered capsaicin derivatives was prepared by using one point modification at the vanillyl-hydroxyl group of capsaicin. All the prepared capsaicinoids were evaluated for their antiproliferative activity against NCI-60 human cancer cell lines at 10 µM. Among the compounds tested, compound 20a exhibited good cytotoxic activity against HCT-116, NCI-H460, and SKOV3 cell lines with IC50 8.55 µΜ, 5.41 µΜ, and 6.4 µΜ, respectively, compared to the parent natural product capsaicin. Further on, it significantly inhibited the colony formation in NCI-H460 in a dose dependent manner and enhanced the ROS effect. It also caused cell arrest at the S phase and induced apoptosis via suppressing the Pro parp marker. Compound 20a exhibited an antimigratory property and suppressed the expression of the VEGF marker in a dose dependent manner. Furthermore, compound 20a also suppressed the effects of the p-Erk, p-p38, and P-CNA makers. In silico studies supported the interaction of this class of compounds with the VEGFR2 protein.

Ginsenoside Rg3 increases nitric oxide production via increases in phosphorylation and expression of endothelial nitric oxide synthase: essential roles of estrogen receptor-dependent PI3-kinase and AMP-activated protein kinase.

We previously showed that ginsenosides increase nitric oxide (NO) production in vascular endothelium and that ginsenoside Rg3 (Rg3) is the most active one among ginseng saponins. However, the mechanism for Rg3-mediated nitric oxide production is still uncertain. In this study, we determined whether Rg3 affects phosphorylation and expression of endothelial nitric oxide synthase (eNOS) in ECV 304 human endothelial cells. Rg3 increased both the phosphorylation and the expression of eNOS in a concentration-dependent manner and a maximal effect was found at 10µg/ml of Rg3. The enzyme activities of phosphatidylinositol 3-kinase (PI3-kinase), c-Jun N-terminal kinase (JNK), and p38 kinase were enhanced as were estrogen receptor (ER)- and glucocorticoid receptor (GR)-dependent reporter gene transcriptions in Rg3-treated endothelial cells. Rg3-induced eNOS phosphorylation required the ER-mediated PI3-kinase/Akt pathway. Moreover, Rg3 activates AMP-activated protein kinase (AMPK) through up-regulation of CaM kinase II and Rg3-stimulated eNOS phosphorylation was reversed by AMPK inhibition. The present results provide a mechanism for Rg3-stimulated endothelial NO production.

Increased ubiquitination of multidrug resistance 1 by ginsenoside Rd.

MCF-7/ADR cells, a doxorubicin-resistant human breast cancer cell line, acquires resistance to several chemotherapeutic agents, such as anthracylines and taxol, via overexpression of the multidrug resistance1 (MDR1) gene. The present study was designed to clarify whether ginsenosides affect the expression of the MDR1 gene in MCF-7/ADR cells. Ginsenoside Rd, Re, Rb1, and Rg1 (100 microg/ml) decreased MDR1 protein levels in MCF-7/ADR cells. In particular, ginsenoside Rd most potently inhibited MDR1 protein expression without cytotoxicity, but did not change mRNA levels or nuclear levels of key transcriptional factors for MDR1 gene expression, hypoxia inducible factor-1alpha, CCAAT-enhancer binding protein beta, Forkhead box-containing protein, O subfamily1, or Y-box binding protein-1. Reporter gene analyses showed that ginsenoside Rd did not decrease MDR1 gene transcription or the pregnane X receptor reporter. MDR1 protein stability is dependent on ubiquitin-dependent protein degradation. We further found that ginsenosides Rd increased ubiquitination of MDR1. Moreover, doxorubicin resistance in MCF-7/ADR cells was reversed by ginsenoside Rd treatment. These results propose that ginseng administration with other anti-cancer agents may be useful for the treatment of chemotherapy-resistant breast cancer through down-regulating MDR1 protein.

Anticancer potency of copper(II) complexes of thiosemicarbazones.

Being a structural and catalytic cofactor in a number of biological pathways, copper accumulates in tumors owing to selective permeability of the cancer cell membranes. Copper(II) ion forms the active centers in a large number of metalloproteins. The coordination of Schiff's base ligands to the metal ion results in the high extent of increase in anticancer activity. The copper(II) complexes can cleave DNA through oxidative and hydrolytic pathways, cell apoptosis via intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway due to excessive production of ROS and hence, are found more active than Ni and Pt complexes. Flexible Cu(I/II) redox behavior helps the copper complexes to form more potent, clinically effective and less toxic copper based antiproliferative drugs of lower IC50 value and higher growth inhibitory activity. Copper(II) complexes of thiosemicarbazones of Isatin, Pyridine, Benzoyl pyridine, Diacetyl/Dimethyl glyoxal, Acetophenone/Acetoacetanalide, Thiazole/Pyrazole, Quinoline, Carboxybenzaldehyde, Cinnamaldehyde/Cuminaldehyde, Citronellal, Chromone, Pyridoxal, 8-Ethyl-2-hydroxytricyclo (7.3.1.02,7) tridecan-13-one, Acyl Diazines, Naphthalene, Proline, 5-Formyluracil, 2-Hydroxy-8-propyltricyclo (7.3.1.02,7) tridecan-13-one, 9-cis-Retinal, Curcumin, Helicin (Salicylaldehyde-ß-D-glucoside), Thiophene carboxaldehyde, Salicylaldehyde, Iminodiacetate, and 3-Formyl-4-hydroxy benzenesulfonic acid have been found to exhibit more anticancer activity toward HCT116, MCF7, A549, U937, HeLa, HepG2, SGC-7901, A2780 cell lines than that of their corresponding thiosemicarbazones and standard topoisomerase-II inhibitors.

Knockdown of CSNK2ß suppresses MDA-MB231 cell growth, induces apoptosis, inhibits migration and invasion.

Breast cancer is the most common cancer among women worldwide. Among different types of breast cancer known, treatment of triple-negative breast cancer is a major challenge because of its aggressiveness and poor prognosis; thus, identification of specific drivers is required for targeted therapies of breast cancer malignancy. Protein Casein Kinase (CSNK) is a serine/threonine kinase that exists as a tetrameric complex consisting of two catalytic (α and /or α') and two regulatory ß subunits. CSNK2ß can also function independently without catalytic subunits and exist as a distinct population in cells. This study aims to elucidate the role of Casein Kinase 2ß (CSNK2ß) gene in cell proliferation, cell cycle, migration and apoptosis of triple-negative breast cancer MDA-MB-231 cells. The silencing of CSNK2ß in MDA-MB-231 cells resulted in decreased cell viability and colony formation. Cell cycle analysis showed a significant arrest of cells in G2M phase. Hoechst and CM-H2DCFDA staining showed nuclear condensation and augmented intracellular reactive oxygen species (ROS) production. Furthermore, silencing of CSNK2ß in MDA-MB-231 cells modulated the apoptotic machinery- BAX, Bcl-xL, and caspase 3; autophagy machinery-Beclin-1 and LC3-1; and inhibited the vital markers (p-ERK, c-Myc, NF-κB, E2F1, PCNA, p38-α) associated with cell proliferation and DNA replication pathways. In addition, knockdown of CSNK2ß also affected the migration potential of MDA-MB-231, as observed in the wound healing and transwell migration assays. Altogether, the study suggests that CSNK2ß silencing may offer future therapeutic target in triple-negative breast cancer.

Inhibition of prostate cancer cell line (PC-3) by anhydrodihydroartemisinin (ADHA) through caspase-dependent pathway.

Cancer is a generic term for a large group of diseases characterized by the growth of abnormal cells, which is the second leading cause of death globally. To treat cancer, currently, a number of anticancer drugs belonging to various classes chemically are available. The discovery of artemisinin and its derivatives such as artesunate, arteether, and artemether became a milestone in the cure for malaria. Here, we report the anti-cancer property of anhydrodihydroartemisinin (ADHA) - a semisynthetic derivative of artemisinin against prostate cancer cell line PC-3. ADHA was found to be inhibiting growth of PC-3 cells. ADHA was also found to be inhibiting migration of PC-3 cells. At molecular level, ADHA was found to be inhibiting the expression of c-Jun, p-c-Jun, p-Akt and NF-κB and activated caspase 3 and 7. The results show that ADHA like few other artemisinin derivatives hold potential to be used as an anti-cancer agent against prostate cancer cells.