Cancer cell plasticity, stem cell factors, and therapy resistance: how are they linked?

Cellular plasticity can occur naturally in an organism and is considered an adapting mechanism during the developmental stage. However, abnormal cellular plasticity is observed in different diseased conditions, including cancer. Cancer cell plasticity triggers the stimuli of epithelial-mesenchymal transition (EMT), abnormal epigenetic changes, expression of stem cell factors and implicated signaling pathways, etc., and helps in the maintenance of CSC phenotype. Conversely, CSC maintains the cancer cell plasticity, EMT, and epigenetic plasticity. EMT contributes to increased cell migration and greater diversity within tumors, while epigenetic changes, stem cell factors (OCT4, NANOG, and SOX2), and various signaling pathways allow cancer cells to maintain various phenotypes, giving rise to intra- and inter-tumoral heterogeneity. The intricate relationships between cancer cell plasticity and stem cell factors help the tumor cells adopt drug-tolerant states, evade senescence, and successfully acquire drug resistance with treatment dismissal. Inhibiting molecules/signaling pathways involved in promoting CSCs, cellular plasticity, EMT, and epigenetic plasticity might be helpful for successful cancer therapy management. This review discussed the role of cellular plasticity, EMT, and stem cell factors in tumor initiation, progression, reprogramming, and therapy resistance. Finally, we discussed how the intervention in this axis will help better manage cancers and improve patient survivability.

Epithelial-to-mesenchymal transition in cancer progression: unraveling the immunosuppressive module driving therapy resistance.

Cancer cells undergo phenotypic switching (cancer cell plasticity) in response to microenvironmental cues, including exposure to therapy/treatment. Phenotypic plasticity enables the cancer cells to acquire more mesenchymal traits promoting cancer cells' growth, survival, therapy resistance, and disease recurrence. A significant program in cancer cell plasticity is epithelial-to-mesenchymal transition (EMT), wherein a comprehensive reprogramming of gene expression occurs to facilitate the translational shift from epithelial-to-mesenchymal phenotypes resulting in increased invasiveness and metastasis. In addition, EMT plays a pivotal role in facilitating cancer cells' escape from the body's immune system using several mechanisms, such as the downregulation of major histocompatibility complex-mediated antigen presentation, upregulation of immune checkpoint molecules, and recruitment of immune-suppressive cells. Cancer cells' ability to undergo phenotypic switching and EMT-driven immune escape presents a formidable obstacle in cancer management, highlighting the need to unravel the intricate mechanisms underlying these processes and develop novel therapeutic strategies. This article discusses the role of EMT in promoting immune evasion and therapy resistance. We also discuss the ongoing research on developing therapeutic approaches targeting intrinsic and induced cell plasticity within the immune suppressive microenvironment. We believe this review article will update the current research status and equip researchers, clinicians, and other healthcare professionals with valuable insights enhancing their existing knowledge and shedding light on promising directions for future cancer research. This will facilitate the development of innovative strategies for managing therapy-resistant cancers and improving patient outcomes.

Role of p53-miRNAs circuitry in immune surveillance and cancer development: A potential avenue for therapeutic intervention.

The genome's guardian, p53, is a master regulatory transcription factor that occupies sequence-specific response elements in many genes and modulates their expression. The target genes transcribe both coding RNA and non-coding RNA involved in regulating several biological processes such as cell division, differentiation, and cell death. Besides, p53 also regulates tumor immunology via regulating the molecules related to the immune response either directly or via regulating other molecules, including microRNAs (miRNAs). At the post-transcriptional level, the regulations of genes by miRNAs have been an emerging mechanism. Interestingly, p53 and various miRNAs cross-talk at different regulation levels. The cross-talk between p53 and miRNAs creates loops, turns, and networks that can influence cell metabolism, cell fate, cellular homeostasis, and tumor formation. Further, p53-miRNAs circuit has also been insinuated in the regulation of immune surveillance machinery. There are several examples of p53-miRNAs circuitry where p53 regulates immunomodulatory miRNA expression, such as miR-34a and miR-17-92. Similarly, a reverse process occurs in which miRNAs such as miR-125b and miR-let-7 regulate the expression of p53. Thus, the p53-miRNAs circuitry connects the immunomodulatory pathways and may shift the pro-inflammatory balance towards the pro-tumorigenic condition. In this review, we discuss the influence of p53-miRNAs circuitry in modulating the immune response in cancer development. We assume that thorough studies on the p53-miRNAs circuitry in various cancers may prove useful in developing effective new cancer therapeutics for successfully combating this disease.

Unveiling the therapeutic promise of natural products in alleviating drug-induced liver injury: Present advancements and future prospects.

Drug-induced liver injury (DILI) refers to adverse reactions to small chemical compounds, biological agents, and medical products. These reactions can manifest as acute or chronic damage to the liver. From 1997 to 2016, eight drugs, including troglitazone, nefazodone, and lumiracoxib, were removed from the market due to their liver-damaging effects, which can cause diseases. We aimed to review the recent research on natural products and their bioactive components as hepatoprotective agents in mitigating DILI. Recent articles were fetched via searching the PubMed, PMC, Google Scholar, and Web of Science electronic databases from 2010 to January 2023 using relevant keywords such as "natural products," "acetaminophen," "antibiotics," "paracetamol," "DILI," "hepatoprotective," "drug-induced liver injury," "liver failure," and "mitigation." The studies reveal that the antituberculosis drug (acetaminophen) is the most frequent cause of DILI, and natural products have been largely explored in alleviating acetaminophen-induced liver injury. They exert significant hepatoprotective effects by preventing mitochondrial dysfunction and inflammation, inhibiting oxidative/nitrative stress, and macromolecular damage. Due to the bioavailability and dietary nature, using natural products alone or as an adjuvant with existing drugs is promising. To advance DILI management, it is crucial to conduct well-designed randomized clinical trials to evaluate natural products' efficacy and develop new molecules clinically. However, natural products are a promising solution for remedying drug-induced hepatotoxicity and lowering the risk of DILI.

Epigenetic modifications of c-MYC: Role in cancer cell reprogramming, progression and chemoresistance.

Both genetic and epigenetic mechanisms intimately regulate cancer development and chemoresistance. Different genetic alterations are observed in multiple genes, and most are irreversible. Aside from genetic alterations, epigenetic alterations play a crucial role in cancer. The reversible nature of epigenetic modifications makes them an attractive target for cancer prevention and therapy. Specific epigenetic alteration is also being investigated as a potential biomarker in multiple cancers. c-MYC is one of the most important transcription factors that are centrally implicated in multiple types of cancer cells reprogramming, proliferation, and chemoresistance. c-MYC shows not only genetic alterations but epigenetic changes in multiple cancers. It has been observed that epigenome aberrations can reversibly alter the expression of c-MYC, both transcriptional and translational levels. Understanding the underlying mechanism of the epigenetic alterations of c-MYC, that has its role in multiple levels of cancer pathogenesis, can give a better understanding of various unresolved questions regarding cancer. Recently, some researchers reported that targeting the epigenetic modifiers of c-MYC can successfully inhibit cancer cell proliferation, sensitize the chemoresistant cells, and increase the patient survival rate. As c-MYC is an important transcription factor, epigenetic therapy might be one of the best alternatives for the conventional therapies that assumes the "one-size-fits-all" role. It can also increase the precision of targeting and enhance the effectiveness of treatments among various cancer subtypes. In this review, we highlighted the role of epigenetically modified c-MYC in cancer cell reprogramming, progression, and chemoresistance. We also summarize the potential therapeutic approaches to target these modifications for the prevention of cancer development and chemoresistant phenotypes.

Lupeol, an androgen receptor inhibitor, enhances the chemosensitivity of prostate cancer stem cells to antiandrogen enzalutamide-based therapy.

Enzalutamide is an androgen receptor (AR) antagonist commonly used in the treatment of prostate cancer (CaP). However, due to the potential toxicity and development of resistance associated with Enzalutamide-based therapy, there is a need to explore additional compounds that can enhance its therapeutic effectiveness while minimizing toxicity. Lupeol is a pharmacologically active triterpene having anticancer effects. The objective of this study was to explore Lupeol's potential in enhancing the chemosensitivity of chemoresistant CaP cells to Enzalutamide in vitro and in a mouse model. To test our hypothesis, we performed cell viability and luciferase reporter gene assay, flow cytometry, animal studies, and histopathological analysis. Finally, we analyzed the change in selective metabolites in the prostate tissue by LCMS. Results demonstrated that a combination of Lupeol and Enzalutamide could better (i) suppress the Cancer Stem Cells (CSCs) and chemoresistant cells (PTEN-CaP8 and PC3) viability and migration, (ii) increase cell cycle arrest, (iii) inhibit the transcriptional activity of AR, c-MYC, c-FLIP, and TCF (iv) inhibit tumor growth in a mouse model (v) protect Enzalutamide-induced adverse effects in prostate glands and gut tissue (vi) decrease levels of testosterone and methionine metabolites. In conclusion, Lupeol enhances the pharmacological efficacy of Enzalutamide and reduces the adverse effects. Thus, Lupeol could be a promising adjuvant for improving Enzalutamide-based treatment outcomes and warrant further research.

Flubendiamide induced genetic and cellular damages directly influence the life cycle of the oriental leaf worm, Spodoptera litura.

Indiscriminate uses of insecticide greatly damage the environment as well as non-target organisms. Thus, multiple levels of bioassays can help better management of our environment. Flubendiamide is a phthalic acid diamide insecticide that ceases the function of insect muscle leading to paralysis and death. Here, we aimed to explore the effects of Flubendiamide on the life cycle of Spodoptera litura vis-a-vis the mode of action. Fourth instar larvae of the same age (120 ± 2 h) and size were fed with different concentrations (20-80 µg/mL) of Flubendiamide for 12-72 h. We performed a pharmacokinetics study, different biochemical assays, p450, Ecdysone receptor (EcR) and other genes expression analyses by Real-Time PCR and gross damages by Dye exclusion assay and histopathology. Our results demonstrate that the mean concentration of Flubendiamide after 48 h is 9.907 µg/mL and (i) altered the molting, metamorphosis, and reproduction at 80 µg/mL (24 h) (ii) increases all oxidative stress parameters (ROS/RNS, MDA, 8OHdG), decreases oxidative defense mechanisms (SOD, CAT, GST) at 80 µg/mL (48 h) and p450 in a time and concentration-dependent manner, (iii) activates CncC/Maf apoptotic pathways at 80 µg/mL concentration at 24 h while the expression declined from 48 h onwards, (iii) downregulates the EcR expression in a time and concentration-dependent manner, which might be responsible for disturbed molting, metamorphosis, and reproduction, and (iv) increase the expression of apoptotic genes (Caspase 1, -3, and - 5), in time and concentration-dependent manner causing gross morphological and histological damages. In conclusion, indiscriminate use of this insecticide can affect the ecosystem and have the capacity to cause multiple hazardous effects on experimental organisms. Thus, it warrants further investigations to improve and optimize the integrated pest management packages, including Flubendiamide for better management.

Antiandrogen enzalutamide induced genetic, cellular, and hepatic damages: amelioration by triterpene Lupeol.

Androgen deprivation therapy is commonly used for the treatment of prostate cancer. Enzalutamide is a next-generation androgen receptor inhibitor, initially approved to treat castration-resistance prostate cancer. Lupeol, a triterpene present in various fruits, vegetables, has anti-oxidant and anti-proliferative activity. The present study aimed to evaluate the Enzalutamide-induced toxicity and its possible amelioration by Lupeol. We performed multiple in vitro and in vivo experiments to conclude our hypothesis. The results revealed that both Enzalutamide and Lupeol interact with DNA through electrostatic interactions. Enzalutamide (5-20 µM) caused cytotoxicity in both normal (PNT2) and cancer cells (LNCaP and 22Rv1). However, Lupeol (10-50 µM) specifically killed the cancer cells while sparing normal cells. The study further revealed that Lupeol could attenuate Enzalutamide-induced cytotoxicity and genotoxicity (chromosomal aberrations and micronucleus formation) to normal cells and potentially induce cytotoxicity to transformed cells. We further observed that Lupeol (40 mg/kg) mediated attenuation of the Enzalutamide (10 mg/kg) induced oxidative and DNA damages. Our study also revealed that Lupeol reverses the Enzalutamide-induced hepatic and renal damages. In conclusion, our study indicates that Lupeol can be used as an adjuvant for reducing the toxic effects and enhancing the effectiveness of Enzalutamide.

Protective effects of a polyherbal medicine, Majoon Suranjan against bisphenol-A induced genetic, oxidative and tissue damages.

Bisphenol-A (BPA) is a toxic chemical largely produced and used in polycarbonate plastics worldwide. Majoon Suranjan (MS), a polyherbal formulation, is used as an anti-inflammatory medicine against rheumatoid arthritis. The present study aimed to evaluate BPA-induced toxicity and its possible amelioration by MS. To test our hypothesis, we performed gas chromatography-mass spectrometry (GC-MS) analysis, DNA interaction studies, genotoxicity tests, oxidative stress parameters, and histopathological examinations. GC-MS profiling of MS revealed the presence of various anti-oxidant compounds. DNA interaction studies showed that both chemicals intercalate between DNA base pairs. Next, we observed BPA-induced genotoxicity and oxidative damage. The observed effects might be due to BPA-induced reactive oxygen species production. Further, BPA changed the anti-oxidant enzyme activities, increased the malondialdehyde, alanine aminotransferase, alkaline phosphatase, and total bilirubin levels, and caused gross damage to the liver and kidney. Interestingly, these effects were significantly reversed by MS. In conclusion, MS shows protective effects against BPA-induced toxicity and could be a potential alternative medicine against BPA toxicity, especially in third-world countries where BPA uses are not strictly regulated.Highlights:Bisphenol-A (BPA) induces multiple toxic effects.BPA induces genotoxicity, oxidative and tissue damage.Majoon Suranjan (MS) ameliorates the BPA induced toxic effects.GC-MS profiling show various active anti-oxidant compounds in MS.MS is anti-genotoxic, anti-oxidant, and hepato-renal protective.

Apigenin alleviates cancer drug Sorafenib induced multiple toxic effects in Swiss albino mice via anti-oxidative stress.

Sorafenib is an FDA-approved chemotherapeutic drug used as standard therapy for advanced-stage cancers. However, Sorafenib-induced multiple adverse effects are a major limitation that directly impacts patients' physical and physiological well-being. Therefore, it is vital to identify agents that can lessen the associated adverse effects and enhance efficacy. Apigenin, a dietary plant flavone, is a bioactive-compound present in fruits and vegetables having anti-oxidant, anti-inflammatory, and anti-cancer properties. Our study aimed to investigate Sorafenib-induced toxic effects at genomic, cellular, and tissue level and the potential protective effects of Apigenin. To achieve our goal, we treated Swiss albino mice with Apigenin (50 mg/kg bw) alone or in combination with Sorafenib (40 mg/kg bw). Next, we performed DNA interaction, genotoxicity, oxidative damages, anti-oxidant activities, liver enzyme levels, and histopathological studies. We demonstrated that Apigenin and Sorafenib bind DNA via electrostatic interaction. Further, Sorafenib induces genetic, oxidative, and tissue damages characterized by an increase in chromosomal aberrations and micronucleus, reactive oxygen species (ROS) and reactive nitrogen species (RNS), oxidative and DNA damage, lipid peroxidation, and hepato-renal damages, and a decrease in antioxidant-enzymes. Interestingly, the Sorafenib-induced adverse effects were ameliorated by Apigenin. Our findings indicate that Apigenin has protective effects against Sorafenib-induced toxicity and could be combined with Sorafenib to lessen its adverse effects and enhance its efficacy. However, further pre-clinical and clinical studies are required to evaluate Apigenin's effectiveness with Sorafenib.

A novel terpenoid class for prevention and treatment of KRAS-driven cancers: Comprehensive analysis using in situ, in vitro, and in vivo model systems.

Inhibiting the disease progression in KRAS-driven cancers after diagnosis has been a difficult task for clinicians to manage due to the lack of effective intervention/preventive therapies. KRAS-driven cancers depend on sustained KRAS signaling. Although developing inhibitors of KRAS signaling has proven difficult in the past, the quest for identifying newer agents has not stopped. Based on studies showing terpenoids as modulators of KRAS-regulated downstream molecular pathways, we asked if this chemical family has an affinity of inhibiting KRAS protein activity. Using crystal structure as a bait in silico, we identified 20 terpenoids for their KRAS protein-binding affinity. We next carried out biological validation of in silico data by employing in situ, in vitro, patient-derived explant ex vivo, and KPC transgenic mouse models. In this report, we provide a comprehensive analysis of a lup-20(29)-en-3b-ol (lupeol) as a KRAS inhibitor. Using nucleotide exchange, isothermal titration calorimetry, differential scanning fluorimetry, and immunoprecipitation assays, we show that lupeol has the potential to reduce the guanosine diphosphate/guanosine triphosphate exchange of KRAS protein including mutant KRASG12V . Lupeol treatment inhibited the KRAS activation in KRAS-activated cell models (NIH-panel, colorectal, lung, and pancreatic intraepithelial neoplasia) and patient tumor explants ex vivo. Lupeol reduced the three-dimensional growth of KRAS-activated cells. The pharmacokinetic analysis showed the bioavailability of lupeol after consumption via oral and intraperitoneal routes in animals. Tested under prevention settings, the lupeol consumption inhibited the development of pancreatic intraepithelial neoplasia in LSL-KRASG12D/Pdx-cre mice (pancreatic ductal adenocarcinoma progression model). These data suggest that the selected members of the triterpene family (such as lupeol) could be exploited as clinical agents for preventing the disease progression in KRAS-driven cancers which however warrants further investigation.

Virtual screening, ADME/T, and binding free energy analysis of anti-viral, anti-protease, and anti-infectious compounds against NSP10/NSP16 methyltransferase and main protease of SARS CoV-2.

Recently, a pathogen has been identified as a novel coronavirus (SARS-CoV-2) and found to trigger novel pneumonia (COVID-19) in human beings and some other mammals. The uncontrolled release of cytokines is seen from the primary stages of symptoms to last acute respiratory distress syndrome (ARDS). Thus, it is necessary to find out safe and effective drugs against this deadly coronavirus as soon as possible. Here, we downloaded the three-dimensional model of NSP10/NSP16 methyltransferase (PDB-ID: 6w6l) and main protease (PDB-ID: 6lu7) of COVID-19. Using these molecular models, we performed virtual screening with our anti-viral, inti-infectious, and anti-protease compounds, which are attractive therapeutics to prevent infection of the COVID-19. We found that top screened compound binds with protein molecules with good dock score with the help of hydrophobic interactions and hydrogen bonding. We observed that protease complexed with Cyclocytidine hydrochloride (anti-viral and anti-cancer), Trifluridine (anti-viral), Adonitol, and Meropenem (anti-bacterial), and Penciclovir (anti-viral) bound with a good docking score ranging from -6.8 to -5.1 (Kcal/mol). Further, NSP10/NSP16 methyltransferase complexed with Telbivudine, Oxytetracycline dihydrate (anti-viral), Methylgallate (anti-malarial), 2-deoxyglucose and Daphnetin (anti-cancer) from the docking score of -7.0 to -5.7 (Kcal/mol). In conclusion, the selected compounds may be used as a novel therapeutic agent to combat this deadly pandemic disease, SARS-CoV-2 infection, but needs further experimental research.HighlightsNSP10/NSP16 methyltransferase and main protease complex of SARS CoV-2 bind with selected drugs.NSP10/NSP16 methyltransferase and protease interacted with drugs by hydrophobic interactions.Compounds show good DG binging free energy with protein complexes.Ligands were found to follow the Lipinski rule of five.

Role of long non-coding RNAs and MYC interaction in cancer metastasis: A possible target for therapeutic intervention.

The c-MYC is one of the most commonly discussed oncogenes in almost all cancers. c-MYC, as a proto-oncogene in normal cells, has found to be tightly controlled and regulated, both genetically and epigenetically. Evasion of the controlled checkpoint mechanisms during cancer causes a deregulated expression of c-MYC. Overexpression of c-MYC causes the onset of many hallmarks of cancer. Despite c-MYC being centrally located in several cancers, it is not feasible to target c-MYC in therapeutic resistant cancers. Similarly, long non-coding RNAs (lncRNAs) are deregulated during the genesis and progression of different cancers. LncRNAs contribute to almost 27% human genome and recent findings by tumor genome sequencing revealed many of the lncRNAs loci that are modified, deleted, amplified, and mutated during the different stages of cancer development. Recent studies also reported that multiple lncRNAs regulate c-MYC by different mechanisms and vice versa. Thus, oncogenic lncRNAs and c-MYC interaction are positioned to provide an interesting choice for therapeutic interventions in cancers. In this mini-review, we summarize the recent discoveries and explain how the interaction between oncogenic lncRNAs and c-MYC could be used as a possible target for therapeutic intervention in cancers, especially the therapeutic resistant metastatic cancers.

Emerging role of long non-coding RNAs in cancer chemoresistance: unravelling the multifaceted role and prospective therapeutic targeting.

Chemotherapy is one of the important treatment modules in early as well as advanced stages of cancer. However, the major limitation of chemotherapy is the development of chemoresistance in the transformed cells of cancer patients, which leads to cancer recurrence. Long non-coding RNAs (lncRNA) are the transcripts longer than 200 nucleotides in length, which are reported to associate with the initiation, progression, recurrence, and metastasis of different cancers. Several lncRNAs have been implicated in the prevalence of chemoresistant phenotypes and also in the restoration of drug sensitivity in chemoresistant cells. LncRNAs such as HOTAIR, H19, and a lot more are involved in the chemoresistance of cancer cells. Therefore, targeting the lncRNAs may serve as a novel strategy for treating chemoresistant cancer. This review throws light on the role of lncRNA in chemoresistance along with the perspective of the therapeutic targets for the treatment of multiple cancers.

Copper (II)-based halogen-substituted chromone antitumor drug entities: Studying biomolecular interactions with ct-DNA mediated by sigma hole formation and cytotoxicity activity.

Copper-based antitumor drug entities 1-3 derived from substituted (F-, Br-, -CH3) 3-formylchromone pharmacophore were synthesized and thoroughly characterized by spectroscopic and single X-ray crystallographic studies. These complexes show structural novelty due to presence of the X-bonds in chromone scaffold which could facilitate higher propensity for nucleic acids via sigma σ-hole interactions. Therefore, structure-activity relationship of 1-3 was studied by performing ct-DNA binding, pBR322 cleavage and cytotoxicity activity to validate their potential to act as chemotherapeutic drug entities. The binding studies of 1-3 with ct- DNA were carried out employing many biophysical techniques and the corroborative results of these experiments showed intercalation mode of binding and the order of binding was found to be 2 > 1 > 3. The structure of drug entities could facilitated strong halogen bonding interaction (in case of 1 &2) and stability of X bond was rationalized by sigma hole region of positive electrostatic potential on the surface of C-X covalent bond, as determined by gas phase B3LYP computational DFT studies. Interestingly, 2 exhibited most avid binding affinity due to presence of Br- electron withdrawing and polarizable group. Further, cleavage studies of 1-3 with pBR322 plasmid DNA were performed which demonstrated significant cleavage activity, the supercoiled form (Form I) of plasmid DNA was converted to nicked form (Form II) with the appearance of linearized form (Form III) in between two, implicating lethal double strand breaks of DNA. 2 showed predominantly higher cleavage activity following the similar trend as observed for binding studies. The cytotoxicity of the complexes 1-3 was evaluated by MTT assay against the human liver carcinoma (Huh-7) and prostate cancer (DU-145) cell lines; complex 2 exhibited specific and selective cytotoxicity for the DU-145 cancer cell line with LC50 value of 1.6 µM.

Hazardous sub-cellular effects of Fipronil directly influence the organismal parameters of Spodoptera litura.

Indiscriminate use of insecticides/pesticides affects the structure and function of the ecosystems. The present study was aimed to investigate the toxic potential of Fipronil (a second generation phenylpyrazole) using Spodoptera litura larvae (Lepidoptera: Noctuidae) as an experimental model. Commercial grade of Fipronil, an insecticide was fed (20-80 mg/L) to the 4th instar larvae of S. litura for 12-72 h and examined different molecular, biochemical and organismal parameters. We observed a significant dose- and time-dependent changes in the biochemical parameters such as Superoxide dismutase (SOD), Glutathione-S-transferase (GST), Catalase (CAT), level of 8-hydroxy 2'-deoxyguanosine (8-OHdG) and Thiobarbituric Acid Reactive Substances (TBARS) [Malondialdehyde (MDA) equivalent] in the exposed larvae. We also observed that Fipronil interacts with DNA. Next, we examined the influence of sub-cellular damages at the organismal level. The alterations in the parameter such as the delayed emergence of larvae, reduced fecundity, fertility and increased rate of malformation in pupae and adults indicate the sub-organismal damages influence at the organismal level. The findings of the present study suggest that discriminatory non-scientific use of insecticide/pesticide might influence the population dynamics of insects and in large ecosystem too and needs further thorough investigations.

NUMB phosphorylation destabilizes p53 and promotes self-renewal of tumor-initiating cells by a NANOG-dependent mechanism in liver cancer.

UNLABELLED: Stem cell populations are maintained through self-renewing divisions in which one daughter cell commits to a particular fate whereas the other retains the multipotent characteristics of its parent. The NUMB, a tumor suppressor, in conjunction with another tumor-suppressor protein, p53, preserves this property and acts as a barrier against deregulated expansion of tumor-associated stem cells. In this context, NUMB-p53 interaction plays a crucial role to maintain the proper homeostasis of both stem cells, as well as differentiated cells. Because the molecular mechanism governing the assembly and stability of the NUMB-p53 interaction/complex are poorly understood, we tried to identify the molecule(s) that govern this process. Using cancer cell lines, tumor-initiating cells (TICs) of liver, the mouse model, and clinical samples, we identified that phosphorylations of NUMB destabilize p53 and promote self-renewal of TICs in a pluripotency-associated transcription factor NANOG-dependent manner. NANOG phosphorylates NUMB by atypical protein kinase C zeta (aPKCζ), through the direct induction of Aurora A kinase (AURKA) and the repression of an aPKCζ inhibitor, lethal (2) giant larvae. By radioactivity-based kinase activity assays, we showed that NANOG enhances kinase activities of both AURKA and aPKCζ, an important upstream process for NUMB phosphorylation. Phosphorylation of NUMB by aPKCζ destabilizes the NUMB-p53 interaction and p53 proteolysis and deregulates self-renewal in TICs. CONCLUSION: Post-translational modification of NUMB by the NANOG-AURKA-aPKCζ pathway is an important event in TIC self-renewal and tumorigenesis. Hence, the NANOG-NUMB-p53 signaling axis is an important regulatory pathway for TIC events in TIC self-renewal and liver tumorigenesis, suggesting a therapeutic strategy by targeting NUMB phosphorylation. Further in-depth in vivo and clinical studies are warranted to verify this suggestion.

ROBO1, a tumor suppressor and critical molecular barrier for localized tumor cells to acquire invasive phenotype: study in African-American and Caucasian prostate cancer models.

High-risk populations exhibit early transformation of localized prostate cancer (CaP) disease to metastasis which results in the mortality of such patients. The paucity of knowledge about the molecular mechanism involved in acquiring of metastatic behavior by primary tumor cells and non-availability of reliable phenotype-discriminating biomarkers are stumbling blocks in the management of CaP disease. Here, we determine the role and translational relevance of ROBO1 (an organogenesis-associated gene) in human CaP. Employing CaP-progression models and prostatic tissues of Caucasian and African-American patients, we show that ROBO1 expression is localized to cell-membrane and significantly lost in primary and metastatic tumors. While Caucasians exhibited similar ROBO1 levels in primary and metastatic phenotype, a significant difference was observed between tumor phenotypes in African-Americans. Epigenetic assays identified promoter methylation of ROBO1 specific to African-American metastatic CaP cells. Using African-American CaP models for further studies, we show that ROBO1 negatively regulates motility and invasiveness of primary CaP cells, and its loss causes these cells to acquire invasive trait. To understand the underlying mechanism, we employed ROBO1-expressing/ROBO1-C2C3-mutant constructs, immunoprecipitation, confocal-microscopy and luciferase-reporter techniques. We show that ROBO1 through its interaction with DOCK1 (at SH3-SH2-domain) controls the Rac-activation. However, loss of ROBO1 results in Rac1-activation which in turn causes E-Cadherin/ß-catenin cytoskeleton destabilization and induction of cell migration. We suggest that ROBO1 is a predictive biomarker that has potential to discriminate among CaP types, and could be exploited as a molecular target to inhibit the progression of disease as well as treat metastasis in high-risk populations such as African-Americans.