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This novel association was restricted to doxorubicin-resistant cells, implicating the protein in therapeutic resistance.
These findings confirm that AHNAK does indeed function in the chemotherapeutic response of breast cancer cells while also emphasizing the need for further investigation into potential implications for AHNAK in terms of predicting and modulating treatment response.
Some of these SNPs have higher frequencies among Southern Africans compared to other African populations and their functionality has only been partially studied.
The cover image, by Asanda C. Disulfiram with or without metformin inhibits oesophageal squamous cell carcinoma in vivo.
Oesophageal squamous cell carcinoma OSCC is highly prevalent in developing countries but there has been little recent progress into efficacious yet affordable treatment strategies.
Drug repurposing is one attractive approach for cancer therapy. This was enhanced by combining DSF with the anti-diabetic drug metformin Met.
This effect for DSF was independent of copper, with no significant accumulation of copper in tumours, together with maintained proteasome activity.
Targeting the oncogenic TBX3 and its co-factors in anti-cancer drug development. Sarcomas are heterogeneous neoplasms of mesenchymal origin whose clinical management is compromised due to inadequate diagnostic markers and limited therapeutic options.
While the incidence rates for sarcomas in Africa remain uncertain, there is a widely held view that they are common in black African children and adolescents.
Indeed, according to a Nigerian study, soft tissue sarcomas make up as much as We recently reported that the transcription factor, TBX3, is overexpressed in a diverse range of sarcoma subtypes where it plays a direct oncogenic role and it has been proposed as a novel target for their treatments.
Direct targeting of transcription factors for therapies however continues to represent a serious challenge and therefore the molecular mechanisms that mediate its biological activity may be more amenable as anti-cancer drug targets.
To address this, affinity purifications coupled with mass spectrometry was performed to identify TBX3 protein co-factors that regulate its oncogenic activity in sarcomas.
The effect of nucleolin on TBX3 function was determined using RNAi rescue experiments coupled with growth curve and scratch motility assays to assess cell proliferation and migration respectively.
Finally, the effect of the nucleolin targeting aptamer, AS, on the cell viability of a range of sarcoma subtypes was tested. Results show that the overexpression of TBX3 and nucleolin are common in a number of sarcoma subtypes.
We provide compelling evidence that nucleolin interacts with and co-operates with TBX3 to promote proliferation and migration of chondrosarcoma, liposarcoma and rhabdomyosarcoma cells.
Furthermore, AS exhibits potent anti-cancer activity in these sarcomas whilst it has no effect on normal cells.
In conclusion, we propose that TBX3 and nucleolin can be used in combination as biomarkers for the diagnosis and targeted therapy of a diverse range of sarcomas which are highly aggressive and treatment resistant cancers.
Targeting the oncogenic TBX3 and its co-factors in anti-cancer drug development [abstract]. A novel palladacycle complex with anti-cancer activity against breast cancer and melanomas also exhibits potent cytotoxicity in a range of sarcomas.
Cisplatin and second-generation alternatives to cisplatin, represent some of the most active and clinically useful agents in the treatment of cancer.
However, their application in the clinic is marred by side-effects and drug resistance. We have identified the binuclear palladacycle, AJ-5, as a lead anticancer compound with potent activity against advanced melanomas and estrogen receptor -positive and -negative breast cancers.
AJ-5 displayed an IC50 of 0. AJ-5 also showed activity against breast cancer stem cells which are associated with drug-resistance and often not targeted by traditional chemotherapeutic agents.
Cytotoxicity assays were performed and sub-micromolar IC50 concentrations were obtained for rhabdomyosarcoma, chondrosarcoma, liposarcoma, synovial sarcoma and osteosarcoma.
Clonogenic assays show that AJ-5 greatly compromises the long-term ability of the sarcoma cells to survive and proliferate.
To determine the underlying molecular mechanisms by which AJ-5 exerts its cytotoxicity, western blot analyses were performed with antibodies to key proteins involved in the DNA damage response in rhabdomyosarcoma cell lines.
AJ-5 treatment also led to autophagy as confirmed by the formation of autophagosomes, increased levels of LC3-II and the presence of LC3 puncta.
Finally, pharmacokinetic studies show that AJ-5 has a promising half-life of Thus the PK data correlates well with our observed efficacy of the drug in our mouse model.
Together these findings suggest that AJ-5 may be an effective chemotherapeutic for treating a range of drug-resistant and advanced cancers.
A novel palladacycle complex with anti-cancer activity against breast cancer and melanomas also exhibits potent cytotoxicity in a range of sarcomas [abstract].
Where have we come from and where are we going? Sarcomas are a heterogeneous group of neoplasms of mesenchymal origin.
To date more than sarcoma subtypes have been identified and they vary in molecular characteristics, pathology, clinical presentation and response to treatment.
Surgery in combination with preoperative and postoperative therapies is the primary treatment for localized sarcoma tumours and is the most promising curative possibility.
Metastasized sarcomas, on the other hand, are treated primarily with single-agent or combination chemotherapy, but this rarely leads to a complete and robust response and often becomes a palliative form of treatment.
The heterogeneity of sarcomas results in variable responses to current generalized treatment strategies.
In light of this and the lack of curative strategies for metastatic and unresectable sarcomas, there is a need for novel subtype-specific treatment strategies.
With the more recent understanding of the molecular mechanisms underlying the pathogenesis of some of these tumours, the treatment of sarcoma subtypes with targeted therapies is a rapidly evolving field.
This review discusses the current management of sarcomas as well as promising new therapies that are currently underway in clinical trials.
Preparation, characterization and evaluation of novel 1,3,5-triazaphosphaadamantane PTA -based palladacycles as anti-cancer agents.
All complexes were fully characterized using IR and NMR spectroscopy, mass spectrometry as well as elemental analysis. In-vitro evaluation of the complexes as anti-cancer agents against the breast-cancer cell lines MCF7 and MDA-MB as well the melanoma cell line ME shows that four of the five complexes tested are active.
These palladacycles exhibit their cytotoxicity by inducing DNA damage which subsequently triggers apoptosis. DNA binding studies using electrophoresis and spectroscopic techniques, such as UV-Vis and circular dichroism spectroscopy, confirms that the palladacycle, C2 definitely interacts with DNA.
Results from these DNA binding experiments seem to rule out co-valent and intercalative binding, pointing rather to a non-covalent interaction, with electrostatic binding being the most likely possibility.
It is envisioned that this would probably involve a hydrolysed or solvated derivative of C2. Metformin-induced alterations in nucleotide metabolism cause 5-fluorouracil resistance but gemcitabine susceptibility in oesophageal squamous cell carcinoma: Metformin-induced resistance to 5-FU.
We show that this is due to global alterations in nucleotide metabolism, including elevated expression of thymidylate synthase and thymidine kinase 1 established 5-FU resistance mechanisms , which likely result in an increase in intracellular dTTP pools and a 'dilution' of 5-FU anabolites.
Metformin treatment also increases deoxycytidine kinase dCK expression and, as the chemotherapeutic agent gemcitabine relies on dCK for its efficient activity, we speculated that metformin would enhance the sensitivity of OSCC cells to gemcitabine.
Indeed we show that metformin pre-treatment greatly increases gemcitabine toxicity and DNA fragmentation in comparison to gemcitabine alone. Taken together, our findings show that metformin alters nucleotide metabolism in OSCC cells and while responsible for inducing resistance to 5-FU, it conversely increases sensitivity to gemcitabine, thereby highlighting metformin and gemcitabine as a potentially novel combination therapy for OSCC.
This article is protected by copyright. The tumour suppressor, miR, inhibits malignant melanoma migration by targetting the TBX3 transcription factor.
The transcription factor, TBX3, is a key driver of malignant melanoma and any drug that impacts its expression is likely to have an impact on the treatment of this highly aggressive and treatment resistant cancer.
Replacement of miRNAs that target oncogenes has gained much attention as a therapy because it is anticipated to be effective with little side-effects since miRNAs are naturally occurring and often target large set of genes in the same oncogenic pathway.
Here we show that miR levels correlate inversely with TBX3 mRNA levels in a panel of melanoma cell lines and in a cohort of patients with primary melanoma.
Low levels of miR and high levels of TBX3 are shown to be associated with poor patient survival. The T-Box transcription factor 3 in development and cancer.
T-box factors comprise an archaic family of evolutionary conserved transcription factors that regulate patterns of gene expression essential for embryonic development.
The T-box transcription factor 3 TBX3 , a member of this family, is expressed in several tissues and plays critical roles in, among other structures, the heart, mammary gland and limbs and haploinsufficiency of the human TBX3 gene is the genetic basis for the autosomal dominant disorder, ulnar-mammary syndrome.
Overexpression of TBX3 on the other hand has been linked to several cancers including melanoma, breast, pancreatic, liver, lung, head and neck, ovarian, bladder carcinomas and a number of sarcoma subtypes.
Furthermore, there is strong evidence that TBX3 promotes oncogenesis by impacting proliferation, tumour formation, metastasis as well as cell survival and drug resistance.
More recently, TBX3 was however shown to also have tumour suppressor activity in fibrosarcomas and thus its functions in oncogenesis appear to be context dependent.
Identification of the upstream regulators of TBX3 and the molecular mechanism s underpinning its oncogenic roles will make valuable contributions to cancer biology.
Synthesis, Structure and Antiproliferative Activity. Research aimed at enhancing the efficacy of organometallic complexes against cancer, has shown that attaching bio-active molecules to metallo drugs often enhances their biological properties.
The antiproliferative activity of the ligands L2 and L3 and complexes C1 to C9 were evaluated in vitro against human promyelocytic leukemia cells HL60 and normal skin fibroblast cells FG0.
The compounds exhibit good activities against HL60 cells and are consistently selective towards cancerous cells over non-tumorous cells.
This study demonstrates the potential of such hybrid compounds to target cancer cells specifically. Jan Encyclopedia of Cancer. Investigating a novel binuclear palladacycle complex for anti-cancer activity in rhabdomyosarcoma cells.
Association of Notch4 with metastasis in human oral squamous cell carcinoma. Despite the development of several therapeutic strategies in the past decades they have failed to improve the survival rate of oral squamous cell carcinoma patients due to the highly metastatic nature of the disease and its high recurrence rate.
However there is accumulating evidence that aberrant Notch4 expression has a critical role in tumorigenesis but its prognostic value and function in OSCC remains uncertain.
This study therefore investigates 1 the expression of Notch4 and its downstream target myelin associated glycoprotein MAG in tissue samples representative of different stages of OSCC with varied clinicopathological features and 2 the possible involvement of Notch4 in the proliferation and migration of OSCC cells.
Further, the metastatic role of Notch4 was analyzed in the HSC-3 cell line by cell proliferation and migration assays. Our study indicates that the aberrant activation of Notch4 promotes OSCC metastasis through perineural spread and ascertains its value as a significant prognostic marker and potential therapeutic target to treat this highly aggressive malignancy.
TBX3, a member of the T-box family of transcription factors, is essential in development and has emerged as an important player in the oncogenic process.
TBX3 is overexpressed in several cancers and has been shown to contribute directly to tumour formation, migration and invasion.
However, little is known about the molecular basis for its role in development and oncogenesis because there is a paucity of information regarding its target genes.
The cyclin-dependent kinase inhibitor p21 WAF1 plays a pivotal role in a myriad of processes including cell cycle arrest, senescence and apoptosis and here we provide a detailed mechanism to show that it is a direct and biologically relevant target of TBX3.
Using a combination of luciferase reporter gene assays and in vitro and in vivo binding assays we show that TBX3 directly represses the p21 WAF1 promoter by binding a T-element close to its initiator.
Furthermore, we show that the TBX3 DNA binding domain is required for the transcriptional repression of p21 WAF1 and that pseudo-phosphorylation of a serine proline motif S located within this domain may play an important role in regulating this ability.
Importantly, we demonstrate using knockdown and overexpression experiments that p21 WAF1 repression by TBX3 is biologically significant and required for TBX3-induced cell proliferation of chondrosarcoma cells.
Results from this study provide a detailed mechanism of how TBX3 transcriptionally represses p21 WAF1 which adds to our understanding of how it may contribute to oncogenesis.
The T-box transcription factor 3 is a promising biomarker and a key regulator of the oncogenic phenotype of a diverse range of sarcoma subtypes.
Sarcomas represent a complex group of malignant neoplasms of mesenchymal origin and their heterogeneity poses a serious diagnostic and therapeutic challenge.
There is therefore a need to elucidate the molecular mechanisms underpinning the pathogenesis of the more than 70 distinguishable sarcoma subtypes.
The transcription factor TBX3, a critical developmental regulator, is overexpressed in several cancers of epithelial origin where it contributes to tumorigenesis by different molecular mechanisms.
However, the status and role of TBX3 in sarcomas have not been reported. Here we show that a diverse subset of soft tissue and bone sarcoma cell lines and patient-derived sarcoma tissues express high levels of TBX3.
We further explore the significance of this overexpression using a small interferring RNA approach and demonstrate that TBX3 promotes the migratory ability of chondrosarcoma, rhabdomyosarcoma and liposarcoma cells but inhibits fibrosarcoma cell migration.
This suggested that TBX3 may play a key role in the development of different sarcoma subtypes by functioning as either an oncoprotein or as a brake to prevent tumour progression.
To further explore this, TBX3 knockdown and overexpression cell culture models were established using chondrosarcoma and fibrosarcoma cells as representatives of each scenario, and the resulting cells were characterized with regard to key features of tumorigenesis.
Results from in vitro and in vivo assays reveal that, while TBX3 promotes substrate-dependent and -independent cell proliferation, migration and tumour formation in chondrosarcoma cells, it discourages fibrosarcoma formation.
Our findings provide novel evidence linking TBX3 to cancers of mesenchymal origin. Furthermore, we show that TBX3 may be a biomarker for the diagnosis of histologically dynamic sarcoma subtypes and that it impacts directly on their oncogenic phenotype.
Indeed, we reveal that TBX3 may exhibit oncogene or tumour suppressor activity in sarcomas, which suggests that its role in cancer progression may rely on cellular context.
Recently palladium Pd complexes have attracted a lot of interest as chemotherapeutic agents because they have been shown to exert a significant cytotoxic effect on cancer cells.
Importantly, Pd complexes have been shown to exert antitumor activity in cisplatin resistant cells and to have less side effects than cisplatin, a widely used platinum-based chemotherapeutic agent.
This led to suggestions that Pd II compounds may have different mechanisms of action from those of cisplatin, but this is still unresolved.
It is, however, generally accepted that the cytotoxic effects exerted by most metal-based compounds result from their capacity to trigger DNA double-strand breaks which activate a canonical DNA damage signaling pathway through activating ataxia telangiectasia mutated ATM , the checkpoint kinase 2 CHK2 , and the tumor suppressor protein p These proteins play an important role in deciding cell fate in response to DNA damage through transactivating the cyclin-dependent kinase inhibitor p21 as well as pro-apoptotic proteins.
While most chemotherapeutic agents have been described to induce cell death via apoptosis, there is increasing evidence that they can also function by initiating mitotic catastrophe and autophagy.
Indeed, several studies have confirmed a complex cross-talk between apoptosis and autophagy, but while some studies indicate that autophagy inhibits the process of apoptosis, others suggest a role for autophagy in the induction of cell death.
It would, however, appear that these opposing roles of autophagy depend, in part, on both the cell type and the chemotherapy used.
Although extraocular muscles are commonly affected by myasthenia gravis MG at presentation, a treatment-resistant ophthalmoplegic complication of MG OP-MG occurs in younger patients with African-genetic ancestry.
Extending this argument, we hypothesized that OP-MG individuals may harbor African-specific polymorphisms in key genes influencing extraocular muscle remodeling.
We screened the regulatory region of the transforming growth factor beta-1 TGFB1 gene encoding the cytokine pivotal in muscle healing responses.
Journal of Human Genetics advance online publication, 3 December ; doi: Sep Advances in Tendon Research: From Bench to Bedside.
The T-box transcription factor, TBX3, is sufficient to promote melanoma formation and invasion. The palladacycle, AJ-5, exhibits anti-tumour and anti-cancer stem cell activity in breast cancer cells.
T-box Transcription Factors in Cancer Biology. The transcription factor, TBX3, is critical for the formation of, amongst other structures, the heart, limbs and mammary glands and haploinsufficiency of the human TBX3 gene result in ulnar-mammary syndrome which is characterized by hypoplasia of these structures.
On the other hand, the overexpression of TBX3 is a feature of a wide range of cancers and it has been implicated in several aspects of the oncogenic process.
This includes its ability to function as an immortalizing gene and to promote proliferation through actively repressing negative cell cycle regulators.
Together this suggests that TBX3 levels may need to be tightly regulated during the cell cycle. The increased levels of TBX3 in S-phase are shown to occur transcriptionally through activation by c-Myc at E-box motifs located at and bps and posttranslationally by cyclin A-CDK2 phosphorylation.
These results suggest that TBX3 is required for cells to transit through S-phase and that this function may be linked to its role as a pro-proliferative factor.
The AKT3 signalling pathway plays a critical role in melanoma formation and invasion and components of this signalling cascade are therefore attractive targets for the treatment of malignant melanoma.
Recent evidence show that the embryonically important TBX3 transcription factor is upregulated in a subset of melanomas and plays a key role in promoting melanoma formation and invasion, in part by repressing the cell adhesion molecule E-cadherin.
Briefly, using site-directed mutagenesis and in vitro kinase assays, we have identified the AKT3 target site at serine residue in the TBX3 protein and show that this site is phosphorylated in vivo.
Importantly, we show by western blotting, immunofluorescence, reporter, migration and invasion assays that the phosphorylation at S promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion.
Our results identify a novel signalling and transcriptional network linking AKT3, TBX3 and E-cadherin during melanoma migration and invasion and reveals TBX3 as a potential target for anti-metastatic therapeutics.
A growing body of work has shown that the highly homologous T-box transcription factors TBX2 and TBX3 play critical but distinct roles in embryonic development and cancer progression.
For example, TBX2 and TBX3 are up-regulated in several cancers and recent evidence suggests that whereas TBX2 functions as a pro-proliferative factor, TBX3 inhibits cell proliferation but promotes cancer cell migration and invasion.
The TBX3 targets responsible for these functions were however not identified. The evolutionarily conserved T-box family of transcription factors have critical and well-established roles in embryonic development.
Of these the best characterised is TBX2, whose expression is upregulated in cancers including breast, pancreatic, ovarian, liver, endometrial adenocarcinoma, glioblastomas, gastric, uterine cervical and melanoma.
Understanding the role and regulation of TBX2, as well as other T-box factors, in contributing directly to tumour progression, and especially in suppression of senescence and control of invasiveness suggests that targeting TBX2 expression or function alone or in combination with currently available chemotherapeutic agents may represent a therapeutic strategy for cancer.
The T-box transcription factor, TBX3, promotes tumourigenesis in soft tissue and bone sarcomas: Genomic instability is a major hallmark of cancer.
To maintain genomic integrity, cells are equipped with dedicated sensors to monitor DNA repair or to force damaged cells into death programs.
The tumor suppressor p53 is central in this process. Here, we report that the ubiquitous transcription factor Upstream Stimulatory factor 1 USF1 coordinates p53 function in making proper cell fate decisions.
USF1 stabilizes the p53 protein and promotes a transient cell cycle arrest, in the presence of DNA damage.
Thus, cell proliferation is maintained inappropriately in Usf1 KO mice and in USF1-deficient melanoma cells challenged by genotoxic stress.
In USF1-deficient cells, the level of p53 can be restored by the re-expression of full-length USF1 protein similarly to what is observed using Nutlin-3, a specific inhibitor that prevents pMDM2 interaction.
Consistent with a new function for USF1, a USF1 truncated protein lacking its DNA-binding and transactivation domains can also restore the induction and activity of p These findings establish that p53 function requires the ubiquitous stress sensor USF1 for appropriate cell fate decisions in response to DNA-damage.
They underscore the new role of USF1 and give new clues of how p53 loss of function can occur in any cell type. Finally, these findings are of clinical relevance because they provide new therapeutic prospects in stabilizing and reactivating the p53 pathway.
The emergence of drug resistant tumours that are able to escape cell death pose a major problem in the treatment of cancers. Combination therapies that induce DNA damage and disrupt the DNA damage repair process may therefore prove to be more effective against such tumours.
The developmentally important transcription factor TBX2 has been suggested as a novel anticancer drug target, as it is overexpressed in several cancers and possesses strong anti-senescence and pro-proliferative functions.
Importantly, we recently showed that when TBX2 is silenced, we are able to reverse several features of transformation in both breast cancer and melanoma cells.
Overexpression of TBX2 has also been linked to drug resistance and we have shown that its ectopic expression results in genetically unstable polyploidy cells with resistance to cisplatin.
Dartster Sharon Prins uit Zoetermeer. De Oranje-dartsters wonnen in Kobe het overall-klassement. En dat was bijzonder, want dat lukte Nederland pas een keer eerder.
Ik kijk altijd gewoon per wedstrijd hoe het gaat. Maar natuurlijk zijn we apetrots op het resultaat. Hier kunnen we echt lang met een goed gevoel op terugkijken.
We lieten kansjes liggen en Zweden profiteerde daar goed van. Thriller 'Maar we zijn echt heel goed positief gebleven en bleven knokken tot het laatste punt', vertelt Prins.
Ook dat werd een thriller. Zenuwen 'Helaas vond de finale een dag later plaats.