Extracellular domain of semaphorin 5A serves a tumor­suppressing role by activating interferon signaling pathways in lung adenocarcinoma cells.

Semaphorin 5A (SEMA5A), which was originally identified as an axon guidance molecule in the nervous system, has been subsequently identified as a prognostic biomarker for lung cancer in nonsmoking women. SEMA5A acts as a tumor suppressor by inhibiting the proliferation and migration of lung cancer cells. However, the regulatory mechanism of SEMA5A is not clear. Therefore, the purpose of the present study was to explore the roles of different domains of SEMA5A in its tumor­suppressive effects in lung adenocarcinoma cell lines. First, it was revealed that overexpression of full length SEMA5A or its extracellular domain significantly inhibited the proliferation and migration of both A549 and H1299 cells using MTT, colony formation and gap closure assays. Next, microarray analyses were performed to identify genes regulated by different domains of SEMA5A. Among the differentially expressed genes, the most significant function of these genes that were enriched was the 'Interferon Signaling' pathway according to Ingenuity Pathway Analysis. The activation of the 'Interferon Signaling' pathway was validated by reverse transcription­quantitative PCR and western blotting. In summary, the present study demonstrated that the extracellular domain of SEMA5A could upregulate genes in interferon signaling pathways, resulting in suppressive effects in lung adenocarcinoma cells.

N-acetyl l-aspartate and Triacetin modulate tumor suppressor MicroRNA and class I and II HDAC gene expression induce apoptosis in Glioblastoma cancer cells in vitro.

Glioblastoma multiforme (GBM), grade IV glioma and is aggressive, malignant primary brain cancer. Altered expression and activity of epigenetic proteins such as histone deacetylases (HDACs) are involved in GBM metastasis. Also, acetates are important to brain metabolites that regulate cell proliferation and apoptosis. Here, we have examined the effect of the acetates on the cell-cycle. U87MG cancer cells treated with N-acetyl l-aspartate (NAA) and sodium acetate have exhibited G1 phase cell-cycle arrest whereas U87MG cells treated with Triacetin (TA), and potassium acetate has induced G2/M cell cycle arrest. We have observed inhibition of histone deacetylase (HDAC) mRNA levels in acetate treated U87MG cells. Interestingly, acetates-treated U87MG cells have shown a significant reduction in the mRNA level of class II HDACs than class I HDACs. Acetate treated cells have exhibited an enhanced expression of various microRNAs such as miR-15b, miR-92, miR-101, miR-155, miR-199, miR-200, miR-223, miR-16, and miR-17 that are involved in the inhibition of cancer cell proliferation, invasion, migration, and angiogenesis. Further, these acetate molecules regulate genes involved in mammalian target of rapamycin complex 2 (mTORC2) such as mammalian stress-activated protein kinase-interacting protein (mSIN1), protein observed with Rictor 2 (Protor 2), and protein kinase C α (PKCα). The present study reveals the possible involvement of the mTORC2 complex during acetate-mediated HDAC inhibition, as well as microRNA modulation. Furthermore, molecular modeling studies were employed to understand the binding mode of these acetate molecules to mTOR, Rapamycin-insensitive companion of mammalian target of rapamycin (Rictor), and HDAC-8 proteins. Thus in this study, we have identified the pivotal role of acetates in the modulation of mTOR complex, epigenetic genes and provide structural as well as functional insights that will help in future drug discovery against GBM cancer therapy.

PAK1 inhibition reduces tumor size and extends the lifespan of mice in a genetically engineered mouse model of Neurofibromatosis Type 2 (NF2).

Neurofibromatosis Type II (NF2) is an autosomal dominant cancer predisposition syndrome in which germline haploinsufficiency at the NF2 gene confers a greatly increased propensity for tumor development arising from tissues of neural crest derived origin. NF2 encodes the tumor suppressor, Merlin, and its biochemical function is incompletely understood. One well-established function of Merlin is as a negative regulator of group A serine/threonine p21-activated kinases (PAKs). In these studies we explore the role of PAK1 and its closely related paralog, PAK2, both pharmacologically and genetically, in Merlin-deficient Schwann cells and in a genetically engineered mouse model (GEMM) that develops spontaneous vestibular and spinal schwannomas. We demonstrate that PAK1 and PAK2 are both hyper activated in Merlin-deficient murine schwannomas. In preclinical trials, a pan Group A PAK inhibitor, FRAX-1036, transiently reduced PAK1 and PAK2 phosphorylation in vitro, but had insignificant efficacy in vivo. NVS-PAK1-1, a PAK1 selective inhibitor, had a greater but still minimal effect on our GEMM phenotype. However, genetic ablation of Pak1 but not Pak2 reduced tumor formation in our NF2 GEMM. Moreover, germline genetic deletion of Pak1 was well tolerated, while conditional deletion of Pak2 in Schwann cells resulted in significant morbidity and mortality. These data support the further development of PAK1-specific small molecule inhibitors and the therapeutic targeting of PAK1 in vestibular schwannomas and argue against PAK1 and PAK2 existing as functionally redundant protein isoforms in Schwann cells.

Overcoming anti-cancer drug resistance via restoration of tumor suppressor gene function.

The cytotoxic anti-cancer drugs cisplatin, paclitaxel, doxorubicin, 5-fluorouracil (5-FU), as well as targeted drugs including imatinib, erlotinib, and nivolumab, play key roles in clinical cancer treatment. However, the frequent emergence of drug resistance severely comprosises their anti-cancer efficacy. A number of studies indicated that loss of function of tumor suppressor genes (TSGs) is involved in the development of cancer drug resistance, apart from decreased drug influx, increased drug efflux, induction of anti-apoptosis mechanisms, alterations in tumor microenvironment, drug compartmentalization, enhanced DNA repair and drug inactivation. TSGs are involved in the pathogenesis of tumor formation through regulation of DNA damage repair, cell apoptosis, autophagy, proliferation, cell cycle progression, and signal transduction. Our increased understanding of TSGs in the past decades demonstrates that gene mutation is not the only reason that leads to the inactivation of TSGs. Loss of function of TSGs may be based on the ubiquitin-proteasome pathway, epigenetic and transcriptional regualtion, post-translation modifications like phosphorylation as well as cellular translocation of TSGs. As the above processes can constitute"druggable targets", these mechanisms provide novel therapeutic approaches in targeting TSGs. Some small molecule compounds targeting these approaches re-activated TSGs and reversed cancer drug resistance. Along this vein, functional restoration of TSGs is a novel and promising approach to surmount cancer drug resistance. In the current review, we draw a scenario based on the role of loss of function of TSGs in drug resistance, on mechanisms leading to inactivation of TSGs and on pharmacological agents acting on these mechanisms to overcome cancer drug resistance. This review discusses novel therapeutic strategies targeting TSGs and offers possible modalities to conquer cancer drug resistance.

Antineoplastic action of sulforaphane on HeLa cells by modulation of signaling pathways and epigenetic pathways.

BACKGROUND: Epigenetic modifications alter signaling and molecular pathways; moreover, they are an important therapeutic target. This study examined the effect of sulforaphane on molecular targets in HeLa cells. METHODS: Quantitative PCR of various molecular targets was performed. Activity of epigenetic enzymes was measured by ELISA and molecular docking analysis was conducted. Promoter methylation of some tumor suppressor genes was quantified using PCR based methylation array. In-silico protein-protein interaction network analysis was performed to understand the effect of transcriptional changes. RESULTS: Quantitative PCR demonstrated the transcriptional modulation of genes involved in proliferation, metastasis, inflammation, signal transduction pathways and chromatin modifiers. Sulforaphane reduced the enzymatic activity of DNA methyl transferases, histone deacetylases and histone methyltransferases. Molecular docking results suggest that sulforaphane competitively inhibited several DNA methyl transferases and histone deacetylases. Promoter 5'CpG methylation levels of selected tumor suppressor genes was found to be reduced which correlated with their transcriptional increase as well modulation of epigenetic enzymes. Further, protein-protein interaction network analysis discerned the participation of genes towards cancer pathways. Functional enrichment and pathway-based analysis represented the modulation of epigenetic and signaling pathways on sulforaphane treatment. CONCLUSIONS: The modulation in transcriptional status of epigenetic regulators, genes involved in tumorigenesis resulting in tumor suppressor genes demethylation and re-expression underscores the mechanism behind the anticancer effect of sulforaphane on HeLa cells.

Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library.

Genetic screening technologies to identify and validate macromolecular interactions (MMIs) essential for complex pathways remain an important unmet need for systems biology and therapeutics development. Here, we use a library of peptides from diverse prokaryal genomes to screen MMIs promoting the nuclear relocalization of Forkhead Box O3 (FOXO3a), a tumor suppressor more frequently inactivated by post-translational modification than mutation. A hit peptide engages the 14-3-3 family of signal regulators through a phosphorylation-dependent interaction, modulates FOXO3a-mediated transcription, and suppresses cancer cell growth. In a crystal structure, the hit peptide occupies the phosphopeptide-binding groove of 14-3-3ε in a conformation distinct from its natural peptide substrates. A biophysical screen identifies drug-like small molecules that displace the hit peptide from 14-3-3ε, providing starting points for structure-guided development. Our findings exemplify "protein interference," an approach using evolutionarily diverse, natural peptides to rapidly identify, validate, and develop chemical probes against MMIs essential for complex cellular phenotypes.

Therapeutic strategies to overcome taxane resistance in cancer.

One of the primary causes of attenuated or loss of efficacy of cancer chemotherapy is the emergence of multidrug resistance (MDR). Numerous studies have been published regarding potential approaches to reverse resistance to taxanes, including paclitaxel (PTX) and docetaxel, which represent one of the most important classes of anticancer drugs. Since 1984, following the FDA approval of paclitaxel for the treatment of advanced ovarian carcinoma, taxanes have been extensively used as drugs that target tumor microtubules. Taxanes, have been shown to affect an array of oncogenic signaling pathways and have potent cytotoxic efficacy. However, the clinical success of these drugs has been restricted by the emergence of cancer cell resistance, primarily caused by the overexpression of MDR efflux transporters or by microtubule alterations. In vitro and in vivo studies indicate that the mechanisms underlying the resistance to PTX and docetaxel are primarily due to alterations in α-tubulin and ß-tubulin. Moreover, resistance to PTX and docetaxel results from: 1) alterations in microtubule-protein interactions, including microtubule-associated protein 4, stathmin, centriole, cilia, spindle-associated protein, and kinesins; 2) alterations in the expression and activity of multidrug efflux transporters of the ABC superfamily including P-glycoprotein (P-gp/ABCB1); 3) overexpression of anti-apoptotic proteins or inhibition of apoptotic proteins and tumor-suppressor proteins, as well as 4) modulation of signal transduction pathways associated with the activity of several cytokines, chemokines and transcription factors. In this review, we discuss the abovementioned molecular mechanisms and their role in mediating cancer chemoresistance to PTX and docetaxel. We provide a detailed analysis of both in vitro and in vivo experimental data and describe the application of these findings to therapeutic practice. The current review also discusses the efficacy of different pharmacological modulations to achieve reversal of PTX resistance. The therapeutic roles of several novel compounds, as well as herbal formulations, are also discussed. Among them, many structural derivatives had efficacy against the MDR phenotype by either suppressing MDR or increasing the cytotoxic efficacy compared to the parental drugs, or both. Natural products functioning as MDR chemosensitizers offer novel treatment strategies in patients with chemoresistant cancers by attenuating MDR and increasing chemotherapy efficacy. We broadly discuss the roles of inhibitors of P-gp and other efflux pumps, in the reversal of PTX and docetaxel resistance in cancer cells and the significance of using a nanomedicine delivery system in this context. Thus, a better understanding of the molecular mechanisms mediating the reversal of drug resistance, combined with drug efficacy and the application of target-based inhibition or specific drug delivery, could signal a new era in modern medicine that would limit the pathological consequences of MDR in cancer patients.

Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia.

Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway. This identifies mTOR as an attractive therapeutic target in HR B-ALL. Here, we report that IKAROS represses MTOR transcription and IKAROS' ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase. Treatment with the CK2 inhibitor, CX-4945, enhances IKAROS activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL. Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with IKAROS-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945). Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from Hispanic/Latino children with HR B-ALL. These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children. The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies.

The human leukocyte antigen as a candidate tumor suppressor.

Here we argue in support of the human leukocyte antigen (HLA) supergene as a tumor suppressor. HLA is a recurring mutational target in a large and diverse group of malignancies. The tumor suppressor function of HLA is linked to an embryonic/stemness and drug resistance phenotype. A deeper understanding of the distinct roles of HLA, including immunosurveillance, stemness, and tumor suppressor functions, could illuminate the limited responses in cancer patients. Furthermore, it would provide guidelines for the design of new therapeutic strategies, including the potential of modulating HLA expression in the tumor stem cell compartment.

Effect of Valproic Acid on the Class I Histone Deacetylase 1, 2 and 3, Tumor Suppressor Genes p21WAF1/CIP1 and p53, and Intrinsic Mitochondrial Apoptotic Pathway, Pro- (Bax, Bak, and Bim) and anti- (Bcl-2, Bcl-xL, and Mcl-1) Apoptotic Genes Expression, Cell Viability, and Apoptosis Induction in Hepatocellular Carcinoma HepG2 Cell Line.

BACKGROUNDS: Hepatocellular carcinoma (HCC), Primary liver cancer, is the fifth most common cancer in men. Histone deacetylation causes chromatin condensation resulting in gene silencing and tumorigenesis. These enzymes have become a novel target for the treatment of cancer. Histone deacetylase inhibitors (HDACIs) can reactivate tumor suppressor genes (TSGs) by inhibition of histone deacetylases (HDACs) activity leads to apoptosis induction in cancer cells. Further, these compounds can induce apoptosis through the intrinsic/mitochondrial pathway. Previously, we reported the effect of valproic acid (VPA) and trichostatin A (TSA) on TSGs p21WAF1/CIP1 (p21), p27Kip1 (p27), and p57Kip2 (P57) and also HDAC1 in colon cancer. The present study was designed to investigate the effect of VPA on the class I histone deacetylase (HDAC) 1, 2 and 3, TSGs p21and p53, and intrinsic mitochondrial pathway, pro- (Bax, Bak, and Bim) and anti- (Bcl-2, Bcl-xL, and Mcl-1) apoptotic genes, viability, and apoptosis in HCC HepG2 cell line. MATERIALS AND METHODS: The HepG2 cells were cultured and treated with VPA. To determine viability, apoptosis, and the relative expression level of the mentioned genes, MTT assay, cell apoptosis assay, and qRT-PCR were done respectively. RESULTS: VPA downregulated class I histone deacetylase (HDAC) 1, 2, and 3, Bcl-2, Bcl-xL, and Mcl-1 and upregulated p21, p53, Bax, Bak, and Bim resulting in apoptosis induction. CONCLUSION: VPA can induce apoptosis via activation of the intrinsic mitochondrial apoptotic pathway and also epigenetic reactivation of p21 and p53 through inhibition of class I HDAC 1, 2 and 3, activity.
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MicroRNA-520c-3p Modulates Doxorubicin-Chemosensitivity in HepG2 Cells.

BACKGROUND: Doxorubicin (DOX) is one of the most common drugs used in cancer therapy, including Hepatocellular Carcinoma (HCC). Drug resistance is one of chemotherapy's significant problems. Emerging studies have shown that microRNAs (miRNAs) could participate in regulating this mechanism. Nevertheless, the impact of miRNAs on HCC chemoresistance is still enigmatic. OBJECTIVE: Investigating the role of microRNA-520c-3p (miR-520c-3p) in the enhancement of the anti-tumor effect of DOX against HepG2 cells. METHODS: Expression profile for liver-related miRNAs (384 miRNAs) has been analyzed on HepG2 cells treated with DOX using qRT-PCR. miR-520c-3p, the most deregulated miRNA, was selected for combination treatment with DOX. The expression level for LEF1, CDK2, CDH1, VIM, Mcl-1 and p53 was evaluated in miR-520c-3p transfected cells. Cell viability, colony formation, wound healing as well as apoptosis assays have been demonstrated. Furthermore, Mcl-1 protein level was measured using the western blot technique. RESULTS: The present data indicated that miR-520c-3p overexpression could render HepG2 cells chemo-sensitive to DOX through enhancing its suppressive effects on proliferation, migration, and induction of apoptosis. The suppressive effect of miR-520c-3p involved altering the expression levels of some key regulators of cell cycle, proliferation, migration and apoptosis, including LEF1, CDK2, CDH1, VIM, Mcl-1 and p53. Interestingly, Mcl-1 was found to be one of the potential targets of miR-520c-3p, and its protein expression level was down-regulated upon miR-520c-3p overexpression. CONCLUSION: Our data referred to the tumor suppressor function of miR-520c-3p that could modulate the chemosensitivity of HepG2 cells towards DOX treatment, providing a promising therapeutic strategy in HCC.

MicroRNA-372-3p Predicts Response of TACE Patients Treated with Doxorubicin and Enhances Chemosensitivity in Hepatocellular Carcinoma.

BACKGROUND: Identification of factors to detect and improve chemotherapy.response in cancer is the main concern. microRNA-372-3p (miR-372-3p) has been demonstrated to play a crucial role in cellular proliferation, apoptosis and metastasis of various cancers including Hepatocellular Carcinoma (HCC). However, its contribution towards Doxorubicin (Dox) chemosensitivity in HCC has never been studied. OBJECTIVE: This study aims to investigate the potential role of miR-372-3p in enhancing Dox effects on HCC cell line (HepG2). Additionally, the correlation between miR-372-3p and HCC patients who received Transarterial Chemoembolization (TACE) with Dox treatment has been analyzed. METHODS: Different cell processes were elucidated by cell viability, colony formation, apoptosis and wound healing assays after miR-372-3p transfection in HepG2 cells Furthermore, the miR-372-3p level has been estimated in the blood of primary HCC patients treated with TACE/Dox by quantitative real-time PCR assay. Receiver Operating Curve (ROC) analysis for serum miR-372-3p was constructed for its prognostic significance. Finally, the protein level of Mcl-1, the anti-apoptotic player, has been evaluated using western blot. RESULTS: We found a significantly higher level of miR-372-3p in the blood of the responder group of HCC patients who received TACE with Dox than of non-responders. Ectopic expression of miR-372-3p reduced cell proliferation, migration and significantly induced apoptosis in HepG2 cells which was coupled with a decrease of anti-apoptotic protein Mcl-1. CONCLUSION: Our study demonstrated that miR-372-3p acts as a tumor suppressor in HCC and can act as a predictor biomarker for drug response. Furthermore, the data referred for the first time its potential role in drug sensitivity that might be a therapeutic target for HCC.

Epigenetic silencing of miR-342-3p in B cell lymphoma and its impact on autophagy.

BACKGROUND: miR-342-3p, localized to 14q32, is a tumor suppressor miRNA implicated in carcinogenesis. Given the presence of a promotor-associated CpG island for its host gene, EVL, we hypothesized that intronic miR-342-3p is a tumor suppressor co-regulated with host gene by promoter DNA methylation in B cell lymphoma. RESULTS: By bisulfite pyrosequencing-verified methylation-specific PCR (MSP), EVL/MIR342 methylation was detected in five (50%) lymphoma cell lines but not normal peripheral blood and tonsils. EVL/MIR342 methylation correlated with repression of both miR-342-3p and EVL in cell lines. In completely methylated SU-DHL-16 cells, 5-AzadC treatment resulted in promoter demethylation and re-expression of miR-342-3p and EVL. In 132 primary lymphoma samples, EVL/MIR342 was preferentially methylated in B cell lymphomas (N = 68; 68.7%) than T cell lymphoma (N = 8; 24.2%) by MSP (P < 0.0001). Moreover, EVL/MIR342 methylation was associated with lower miR-342-3p expression in 79 primary NHL (P = 0.0443). In SU-DHL-16 cells, the tumor suppressor function of miR-342-3p was demonstrated by the inhibition of cellular proliferation and increase of cell death upon over-expression of miR-342-3p. Mechanistically, overexpression of miR-342-3p resulted in a decrease of LC3-II, a biomarker of autophagy, which was pro-survival for SU-DHL-16. Pre-treatment with 3-methyladenine, an autophagy inhibitor, abrogated tumor suppression associated with miR-342-3p overexpression. By luciferase assay, MAP1LC3B, a precursor of LC3-II, was confirmed as a direct target of miR-342-3p. Finally, in SU-DHL-16 cells, overexpression of miR-342-3p downregulated the known target DNMT1, with promoter demethylation and re-expression of tumor suppressor E-cadherin. CONCLUSIONS: Intronic miR-342-3p is co-regulated with its host gene EVL by tumor-specific promoter DNA methylation in B cell lymphoma. The tumor suppressor function of miR-342-3p was mediated via inhibition of pro-survival autophagy by targeting MAP1LC3B and downregulation of DNMT1 with demethylation and re-expression of tumor suppressor genes.

Participation of MicroRNAs in the Treatment of Cancer with Phytochemicals.

Cancer is a global health concern and one of the main causes of disease-related death. Even with considerable progress in investigations on cancer therapy, effective anti-cancer agents and regimens have thus far been insufficient. There has been compelling evidence that natural phytochemicals and their derivatives have potent anti-cancer activities. Plant-based anti-cancer agents, such as etoposide, irinotecan, paclitaxel, and vincristine, are currently being applied in medical treatments for patients with cancer. Further, the efficacy of plenty of phytochemicals has been evaluated to discover a promising candidate for cancer therapy. For developing more effective cancer therapy, it is required to apprehend the molecular mechanism deployed by natural compounds. MicroRNAs (miRNAs) have been realized to play a pivotal role in regulating cellular signaling pathways, affecting the efficacy of therapeutic agents in cancer. This review presents a feature of phytochemicals with anti-cancer activity, focusing mainly on the relationship between phytochemicals and miRNAs, with insights into the role of miRNAs as the mediators and the regulators of anti-cancer effects of phytochemicals.

Altered tumor suppressor genes expression in Egyptian pesticide applicators exposed to organophosphate insecticides.

Occupational exposure in spraying and application of non-arsenical insecticides has been classified as a probable human carcinogen. The fundamental molecular mechanisms involved the tumor-related genes. This study aimed to investigate the carcinogenesis effects related to chronic exposure to organophosphate (OP) pesticides in pesticide applicators. This was a cross-sectional study conducted on 27 pesticide applicators and 24 matched controls through the period from June to December 2018. The level of acetylcholinesterase (AChE) was determined and the effects of OPs exposure on messenger RNA (mRNA) expression of the DNA-damage responsive genes P53, P21, GADD45a, and MDM2 were determined using real-time quantitative polymerase chain reaction. A significant reduction of serum AChE enzyme activities was observed in chronically exposed subjects in comparison with the control group (p = 0.001). The expression of P53, P21 mRNA was significantly downregulated in the exposed group compared with the healthy nonexposed control group (p < 0.05). Conversely, the expression of MDM2 and GADD45a did not significantly differ between the exposed subjects and the control group (p > 0.05). No significant differences were noted between the exposed and control groups regarding the genotype or allele distributions of P53 Arg72Pro polymorphism. These results suggested that chronic exposure to OP insecticides may have mitogenic and carcinogenicity activity for the exposed cases due to downregulation of P53 and P21 but did not demonstrate any DNA damage properties for the exposed cases, and finally, a regular follow-up of the exposed cases for tumor markers is recommended.

The effect of oleuropein on apoptotic pathway regulators in breast cancer cells.

In spite of advancements in breast cancer therapy, this disease is still one of the significant causes of women fatalities globally. Dysregulation of miRNA plays a pivotal role in the initiation and progression of cancer. Therefore, the administration of herbal compounds with anticancer effects through controlling microRNA expression can be considered as a promising therapy for cancer. Oleuropein is the most prevalent phenolic compound in olive. Given its domestic consumption, low cost, and nontoxicity for human beings, oleuropein can be used in combination with the standard chemotherapy drugs. To this end, we examined the effect of oleuropein on two breast cancer cell lines (MCF7 and MDA-MB-231). Our findings revealed that oleuropein significantly decreased cell viability in a dose- and time-dependent manner, while it increased the apoptosis in MCF7 and MDA-MB-231 cells. In the presence of oleuropein, the expression levels of miR-125b, miR-16, miR-34a, p53, p21, and TNFRS10B increased, while that of bcl-2, mcl1, miR-221, miR-29a and miR-21 decreased. The findings pointed out that oeluropein may induce apoptosis via not only increasing the expression of pro-apoptotic genes and tumor suppressor miRNAs, but also decreasing the expression of anti-apoptotic genes and oncomiR. Consequently, oleuropein can be regarded as a suitable herbal medication for cancer therapy.

An Insight of Scientific Developments in TSC for Better Therapeutic Strategy.

Tuberous sclerosis complex (TSC) is a rare genetic disease, which is characterized by noncancerous tumors in multi-organ systems in the body. Mutations in the TSC1 or TSC2 genes are known to cause the disease. The resultant mutant proteins TSC1 (hamartin) and TSC2 (tuberin) complex evade its normal tumor suppressor function, which leads to abnormal cell growth and proliferation. Both TSC1 and TSC2 are involved in several protein-protein interactions, which play a significant role in maintaining cellular homeostasis. The recent biochemical, genetic, structural biology, clinical and drug discovery advancements on TSC give a useful insight into the disease as well as the molecular aspects of TSC1 and TSC2. The complex nature of TSC disease, a wide range of manifestations, mosaicism and several other factors limits the treatment choices. This review is a compilation of the course of TSC, starting from its discovery to the current findings that would take us a step ahead in finding a cure for TSC.

Understanding the Monoclonal Antibody Involvement in Targeting the Activation of Tumor Suppressor Genes.

Monoclonal antibodies (mAbs) have always provided outstanding therapeutic arsenal in the treatment of cancer, be it hematological malignancies or solid tumors. Monoclonal antibodies mediated targeting of cancer genes in general and tumor-suppressor genes, in particular, have appreciably allowed the possibilities of trafficking these antibodies to specific tumor mechanisms and aim for the pin-point maneuvered tumor treatment strategies. The conventional cancer treatment options are associated with enormous limitations like drug resistance, acute and pan-toxic side effects and collateral damage to other unrelated cells and organs. Therefore, monoclonal antibody-mediated treatments have some special advantages of specific targeting of cancer-related genes and minimizing the off-target side effects. A large number of monoclonal antibody-mediated treatment regimen viz. use of immunoconjugates, clinically targeting TGFß with pan-TGFß monoclonal antibodies, p53 by its monoclonal antibodies and EGFRtargeted monoclonal antibodies, etc. have been observed in the recent past. In this review, the authors have discussed some of the significant advances in the context of targeting tumor suppressor genes with monoclonal antibodies. Approximately 250 articles were scanned from research databases like PubMed central, Europe PubMed Central and google scholar up to the date of inception, and relevant reports on monoclonal antibody-mediated targeting of cancer genes were selected. mAb mediated targeting of tumor suppressor genes is a recent grey paradigm, which has not been explored up to its maximum potential. Therefore, this review will be of appreciable significance that it will boost further in-depth understanding of various aspects of mAb arbitrated cancer targeting and will warrant and promote further rigorous research initiatives in this regard. The authors expect that this review will acquaint the readers with the current status regarding the recent progress in the domain of mAbs and their employability and targetability towards tumor suppressor genes in anti-cancer therapeutics.

Reduced expression of CYLD promotes cell survival and inflammation in gefitinib-treated NSCLC PC-9 cells: Targeting CYLD may be beneficial for acquired resistance to gefitinib therapy.

The application of tyrosine kinase inhibitors (TKIs) to the epidermal growth factor receptor (EGFR) has been proven to be highly effective for non-small-cell lung cancer (NSCLC). However, patients often evolve into acquired resistance. The secondary mutations in EGFR account for nearly half of the acquired resistance. While the remaining 50% of patients exhibit tolerance to EGFR-TKIs with unclear mechanism(s). Cylindromatosis (CYLD), a deubiquitinase, functions as a tumor suppressor to regulate cell apoptosis, proliferation, and immune response, and so on. The role of CYLD in NSCLC EGFR-TKI resistance remains elusive. Here, we found CYLD was upregulated in PC-9 cells, whereas downregulated in PC-9 acquired gefitinib-resistant (PC-9/GR) cells in response to the treatment of gefitinib, which is consistent with the results in the Gene Expression Omnibus database. Overexpression of CYLD promoted a more apoptotic death ratio in PC-9/GR cells than that in PC-9 cells. In addition, silencing the expression of CYLD resulted in an increase of the expression level of interleukin-6, transforming growth factor-ß and tumor necrosis factor-α, which may contribute to acquired resistance of PC-9 cells to gefitinib. Taken together, our data in vitro demonstrate that PC-9/GR cells downregulated CYLD expression, enhanced subsequent CYLD-dependent antiapoptotic capacity and inflammatory response, which may provide a possible target for acquired gefitinib-resistant treatment in NSCLC.