| 2014 | 2012 | 2011 | 2010 |
Human papillomaviruses are the main cause of cervical cancer. However, exposure to the virus alone is not enough to cause cancerous tumor growth. In this paper, Leung et al explore the roles of miRNA, specifically miR-135a, SIAH1 and β-catenin in the cause of cervical cancer.
They first investigated the action of miR-135a by forcing its expression in cells. They found cells more readily form colonies and have an increased rate of proliferation. The cellís migratory abilities also increased with the forced expression of miR-135a. In the absence of oncoproteins E6 and E7, cells tend to have more normal behavior even in the presence of miR-135a forced expression showing these proteins are facilitate the enhancement of certain cancerous behaviors in cells.
SIAH1 was found to have a higher rate of expression in the NC104-E6/E7 cells. The role of SIAH1 in cervical cancer was determined to be mediating the action of miR-135a to upregulate the expression of β-catenin. The knockout of β-catenin lowers the amount of cell colonies formed. Thus, showing its role in the formation of cancer.
Showing the roles of miR-135a, E6/E7 proteins, SIAH1 and β-catenin in the formation of cervical cancers shows many different target molecules that can be used to treat cervical cancers.
Links related to the paper:
MicroRNAs: Target Recognition and Regulatory Functions
Serine Phosphorylation-regulated Ubiquitination and Degradation of β-Catenin
In a quest to better understand the pathway following oncogenic KRAS expression in non-small cell lung carcinomas, Blasco et al. employed systematic mutations the Raf/Mek/Erk pathway componentsó hoping to identify a possible target for future cancer therapy.
The researchers first targeted ERK1 and ERK2 in tracheal regions of mice with oncogenic KRAS. While individual knockdowns of these genes had minimal effect, a knockdown of ERK1 & ERK2 simultaneously resulted in an increased life span compared to mice with oncogenic KRAS and without ERK ablations. However, when testing homeostatic role of ERK1/2 through widespread excision, mutant mice revealed multiple organ failures and died within 3 weeks. While the double knockdown of ERK1 & ERK2 helps diminish tumor development in isolated regions, it also proves to be necessary to normal homeostasis.
When looking at MEK1/2 kinase genes, similar results were found. First, there was minimal impact on tumor development/life span with the knockdown of a single MEK gene. Second, mice with oncogenic KRAS and localized double MEK1/2 knockdowns had increased life spans. Third, MEK1 and MEK2 are necessary for maintaining homeostasisó widespread MEK excision will cause major problems. Ablations of both MEK kinases, all else being equal, lead to an unfortunately stunted life span.
Blasco et al then turned their attention to Raf kinases, specifically B-Raf and C-Raf. Ablation of B-Raf in mice with oncogenic KRAS did not effect life span or tumor development. However, mice with mutant C-Raf showed an increased survival time and decreased tumor growth. Further, widespread systematic depletion of C-Raf did not induce lethal consequences (even when paired with simultaneous excision of B-Raf). The authors explain that these results should lead to further exploration of C-Raf as a therapeutic possibility to non-small cell lung carcinoma.
Links related to the paper:
Raf Kinases: Function, Regulation and Role in Human Cancer
New Insight Puts CRAF in Sight as a Therapeutic Target
Clinical Relevance of KRAS in Human Cancers
All-trans retinoic acid (ATRA) has been studied intensely for its role in chemopreventive schemes in a multiple tumoral diseases. It is also thought to inhibit carcinogenesis by the form of blocking initiated/transformed cells through three mechanisms: inducing of apoptosis, arrest of abnormal cell growth and differentiation of irregular cells into normal cells. P16 and p14 are silenced in human tumors such as hepatocellular carcinoma (HCC) by DNA methylation. DNA methylation can assist with regulation of ATRA and acts as a gene regulatory mechanism, ATRA downregulates and therefore decreases DNMTs activity.
Shin-Hee et al. wanted to understand and experiment to see if ATRA can differentially induce apoptosis in hepatoma cells dependent on p53 availability, and if so does ATRA necessarily need p53 to activate an apoptotic pathway that could lead to cell death.
Using various techniques such as MTT assays, cell cycle profiles, western blotting, and PCR the scientists tested their hypotheses. ATRA was found to induce apoptosis in p53+ hepatoma cells in humans by MTT assay. This led to Shin Hee et al. to conduct a follow up experiment that showcased ATRA upregulating p53 levels from activating the p14-MDM2-p53 pathway. P14 expression conducted via promoter hypomethylation is essential for ATRA induced apoptosis. This research is quite important as ATRA could be used as a treatment in cancer.
Links related to the paper:
All trans retinoic acid in acute promyelocytic leukemia
DNA hypomethylation in cancer cells
p53 family and cellular stress response in cancer-nice figure
Differences between HepG2 and Hep3B cells
This paper presents the finding that restoring p53 activity leads to tumor regression in high-grade lesions, but does not affect early low-grade lesions.
Researchers used mice in which tumorigenesis was driven by mutant Kras and p53 inactivation (KrasLA2/+;Trp53LSL/LSL;Rosa26CreERT2 mice). The expression of p53 was restored through the addition of tamoxifen at different times during tumor progression. At 4 weeks, when most of the lesions were adenomas, p53 activation had no effect on tumor size or number. At 10 weeks, when mice exhibited adenomas, adenocarcinomas, and mixed tumors, restoration of p53 led to a reduction in the size of tumors. Researchers found that at this time, restoration of p53 expression only caused the regression of the the adenocarcinomas, but not the adenomas. They proposed that this could be due to low levels of oncogenic Kras signaling in adenomas which are not sufficient to induce the activity of the p53 pathway. Progression to adenocarcinomas involves higher Kras signaling and may activate p53 though MAPK and Arf, and therefore lead to the outgrowth of cells with inactivated p53. So, Arf expression was necessary for the tumor-inhibitory effects of p53 restoration. The reactivation of p53 in these cells induced senescence, probably through p21.
The results of this study have significant implications for cancer therapy because the reactivation of p53 could result in incomplete tumor regression, leaving behind early grade lesions that could then progress. Targeting these high-grade lesions may award a significant therapeutic advantage, but additional strategies that can eliminate the low-grade lesions should also be developed in order to obtain a complete therapeutic response.
Links related to the paper:
Activation of Kras causes early lung cancer in mice
Restoration of p53 function leads to tumor regression
The function and importance of p53
The p63 gene is a member of the p53 gene family that functions in squamous epithelia, including the esophagus. It is a transcription factor that encodes for two major isoforms, TAp63 and ΔNp63. TAp63 functions in apoptosis, while ΔNp63 is involved in skin development and stem cell regulation. Studies with p63 knockout mice demonstrate its role in maintenance of proliferation, and normal expression is required for esophageal differentiation and morphogenesis.
Overexpression of p63 has been observed in esophageal squamous carcinomas (ESC). Increasing the expression of p63 results in a more aggressive phenotype, as invasion and metastasis are stimulated. While it was known that p63 stimulates ESC cell growth by activation of the Akt signaling pathway, Lee et al. aimed to elucidate the mechanism of ESC cell adhesion and invasion.
A wound healing assay and Matrigel invasion assay were performed to observe the effect of p63 on ESC cell migration and invasion, respectively. This was done using human ESC cell lines that either silenced or overexpressed p63. It was found that p63 regulates the mRNA and protein expression of several molecular markers of invasion and migration, including vimentin, twist and uPA. The migration of ESC cells via β-catenin and c-Myc is also promoted by p63, as they are both activated with the overexpression of p63.
The authors state that with further research to gain a better understanding of the complex mechanisms involved in p63-promoted metastasis, this gene could be a target in developing a therapeutic strategy for ESC.
Links related to the paper:
p63 Expression Profiles in Human Normal and Tumor Tissues
Elevated expression of p63 protein in human esophageal squamous cell carcinomas
Akt Pathway Diagrams and Overview
While Ras-type mutants have been identified in multiple types of melanomas and other cancers, NRAS mutants do not currently have successful therapeutic treatments. Kwong et al. have demonstrated that combination drug therapy has been useful in mimicking NRAS inhibition, as NRAS inhibition has proven effective in in vitro experiments but has been unsuccessful in human cancer trials.
First and foremost, the classical single amino acid mutation in Ras, NRAS-Q61K, is known to be the cause of cancerous activity in many melanomas. In mouse models where NRAS-Q61K is induced by synthetic promoters and doxycycline administration (iNRAS) and NRAS-Q61K expression is repressed by doxycycline withdrawal, tumor regression was complete in around 10 days on average. With this understanding, they sought to find different components of the RTK pathway and potentially different pathway members that could mimic this regression. In their research, they found that MEK inhibition was able to induce apoptosis in RNAS mutant melanoma, but was unable to halt the cell cycle and cause tumor regression. They hypothesized that a different pathway must be inactivated by knock-down of NRAS-Q61K to halt the cell cycle progression to promote full tumor regression.
Using a transcriptional regulatory associations in pathways (TRAP) online algorithm, Kwong et al. constructed a network with over 3000 public microarrays, and ran statistical tests to find the genes that had the most amount of regulation or deregulation compared to their microarray of iNRAS system. They found that Cdk4 (cyclin-dependent kinase 4), a well-known regulator of G1/S cell-cycle checkpoint, was most effected by iNRAS knock-down, but not MEK inhibition. They further used western blot analysis and gene knock-down and knock-in experiments to confirm their findings.
This research has important clinical implications, showing that signaling pathways that may have once thought to be purely canonical can function non-canonically over gradients of expression to activate other protein products. The online TRAP methods and public microarray databases also provide essential information for delineating non-canonical pathway players.
Links related to the paper:
Supplementary Figures to Kwong et al. Paper
Time-series RNA-seq analysis package (TRAP) - This article has background information relating to TRAP, one of the online methods used in Kwong et al.
CDKN2 (p16/MTS1) Gene Deletion or CDK4 Amplification Occurs in the Majority of Glioblastomas - Provides information regarding previous identification of Cdk4 in cancerous cells.
Essential role for oncogenic Ras in tumour maintenance Previous work on Ras in cancer. Can be accessed through SALLY via USD.
Development of Human Protein Reference Database as an Initial Platform for Approaching Systems Biology in Humans Provides a general overview to the use of systems biology
The sonic hedgehog (SHH) signaling pathway is known to have a major role in the development of vertebrates, especially in cell proliferation and maintenance. Due to these specific and largely important tasks, many cancers are also linked to the SHH signaling pathway such as; basal-cell carcinoma, esophageal and stomach cancer, small-cell lung cancer and pancreatic adenocarcinoma. But what about this pathway causes these cancers and also leads to the growth of tumors after radiation therapy has taken place?
Ma et al. wanted to examine the roles that the SHH signaling pathway has in dying cell stimulated tumor cell growth. They also wanted to figure out how to target the pathway so that suppression of tumor cell repopulation may aid in the success of radiotherapy and chemotherapy in the future.
In using irradiated cells as 'feeder cells' and non-irradiated cells as 'reporter cells,' Ma et al., found that the dying tumor cells, the feeders, were actively releasing an SHH signal and that the neighboring reporter cells, the living cells that did not undergo radiation, were proliferating. Overall, several SHH pathway antagonists, including a Gli1 antagonist, Glant61, and a knock-down of transcription factor Gli1, were found to decrease tumor cell multiplication. There were, however, antagonists that showed no significant decrease in tumor growth within the two different tumor cell types used, a pancreatic tumor cell line (Panc1) and a colonic tumor cell line (HT29).
Links related to the paper:
Radiation Therapy Principles - The cellular reactions that take place during radiation therapy in cancer patients.
Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy - Dying tumor cell stimulated living tumor cell growth during radiation therapy.
It is known that both autophagy and apoptosis play important developmental roles in animals, and specifically, Caenorhabditis elegans. This paper shows that various pharmocological and genetic treatments cause embryonic lethality in C. elegans due to a cell death response orchestrated by both apoptosis and autophagy.
DNA damage involving incorrect incorporation of Uracil instead of Thymine is normally repaired by the DNA base excision repair pathway. However, if the amount of damage exceeds the pathway's capacity to excise Uracil and add Thymine, PCD is activated to eliminate the defective cell. In dut-1 C. elegans mutants, this mutation of the base excision repair pathway led to highly increased autophagic activity. This concludes that geneotoxic stress leads to the massive upregulation of autophagy genes.
In the successful development of viable C. elegans embryos, the apototic and autophagic processes are required redundantly. In a loss of function (lf) mutation for only the ced-4 gene required for apoptosis, no significant affects of phenotype were observed. Similarly, in lf ced-3 mutants, hermaphrodites displayed the normal phenotype and produced viable progeny. This was observed in single lf mutations of autophagy genes as well. In double mutants with lf mutations in both apoptotic and autophagic genes, a highly penetrant embryonic and larval lethality resulted.
Autophagic and apoptotic processes are evolutionarily conserved across divergent animal phyla with gene homologs identified in humans a well as other vertebrates. The shared roles of apoptosis and autophagy discovered in C. elegans might help us to understand how dysregulated PCD in humans can lead to diverse pathologies, including diabetes, cancer, and some neurodegenerations.
Links related to the paper:
Inactivation of the autophagy gene bec-1 triggers apoptotic cell death in C. elegans.
Autophagy genes function in apoptotic cell corpse clearance during C. elegans embryonic development.
http://www.ncbi.nlm.nih.gov/pubmed/22653037
In the event of apoptosis, several 'eat me' signals trigger phagocytic cells to internalize and degrade dying cells. Phagocytes recognize dying cells either from their receptors or through bridging molecules. The purpose of this paper was to identify the specific mechanism that is related to how dying cells are removed via phagocytosis. Their results indicated that TTR-52 was an essential protein that was required to mediate the recognition and engulfment of apoptotic cells.
In nematode Caenorhabditis elegans there are two signaling pathways that control the process of phagocytosis of apoptotic cells. One of the pathways includes the ced-1, ced-6, and ced-7 genes that function in recognizing the 'eat me' signal. CED-1 is encoded from the gene ced-1; it plays a role in recognizing apoptotic cells. The 'eat me' signal that is recognized by CED-1 is the phospholipid phosphatidyl serine (PtdSer), which is present in the surface of apoptotic cells.
CED-1 is not known to bind directly to PtdSer. However, TTR-52 (a member of the transthyretin-like protein family) was observed to be essential to mediate and bridge between CED-1 and PtdSer. To show that cell engulfment requires TTR-52, the authors isolated a recessive mutant, sm211, which enhanced engulfment defect and increased the presence of cell corpses. This mutant affected the function of the gene ttr-52, which encodes TTR-52, that function in the ced-1, ced-6, and ced-7pathway. They also proved that TTR-52 is a secretory protein that binds to apoptotic cells. By using TTR-52-GFP fusion under the control of the C. elegans heat-shock promoters, they detected TTR-52 on the surface of apoptotic cells. Moreover, they also observed that TTR-52 is secreted from the intestine of C. elegans, which diffuses and binds to apoptotic cells to promote their engulfment and degradation. To confirm that TTR-52 mediates recognition of apoptotic cells by CED-1, they used both TTR-52-mCherry and CED-1-GFP fusions. The authors observed that both stains were overlapping, and that TTR-52-mCherry formed a ring, around apoptotic cells, which preceded the ring formed by CED-1-GFP.
The authors then searched for a mutation that would alter the staining of TTR-52-mCherry to apoptotic cells. They found one mutation, qx30, which is an allele of tat-1 (loss of function) that caused all cells (normal and apoptotic) to be labeled by TTR-52-mCherry. In tat-1 (loss of function) mutation, PtdSer is ectopically exposed on the surface of many living cells. This provides direct evidence that TTR-52 binds to PtdSer in plasma membrane. Therefore, the gene ttr-52 was found to be responsible for encoding a secretory protein that acts in the CED-1 signaling pathway to mediate the engulfment of apoptotic cells by bridging CED-1 with the PtdSer signal, in C. elegans. Nevertheless, because ttr-52(sm211) induces a weak engulfment defect, other possible bridging molecules and/or 'eat me' signals could have similar roles to TTR-52 in apoptosis.
Links related to the paper:
Apoptosis: why and how does it occur in biology?
Apoptosis: A Programme of Cell Death or Cell Disposal?
CED-1 Is a Transmembrane Receptor that Mediates Cell Corpse Engulfment in C. elegans
WormBook: Programmed cell death
Engulfment of apoptotic cells: signals for a good meal
During apoptosis, caspases catalyze the cleavage of several enzymes involved in DNA replication and maintenance, such as DNA-dependent protein kinase or DNA topoisomerase II. However, the fate of ribnonucleotide reductase (RnR), an enzyme that converts ribonucleotides to deoxyribonucleotides to be used in DNA synthesis, was unknown. RnR is a heterodimer, composed of an R1 subunit and either an R2 or the closely related p53R2 subunit.
Tebbi et al. sought to understand the role fate of RnR during apoptosis. Using immunoblotting, they observed the R1 and p53R2 subunits in apoptotic cells and found that, while the R1 subunit appears to be unaffected, p53R2 is cleaved at the C-terminal, a region necessary for proper binding to R1, during apoptosis. This cleavage was found to be caspase-dependent, as adding an anti-caspase drug blocked the cleavage.
Using computer modeling, the researchers found the most probable sight of cleavage to be in a sequence conserved across all mammals, and that caspases 3 and 8 were most likely to cleave. The role of caspase 3 and 8 in cleavage was confirmed by knocking down caspases selectively using siRNA. Ultimately, however, because caspase 8 cleaves procaspase 3 into caspase 3, they were unable to determine if caspase 8 cleaved p53R2 itself or simply enabled its cleavage by caspase 3. The study allowed for a more detailed understanding of how caspases halt DNA replication and repair in apoptotic cells.
Links related to the paper:
Old, new, and emerging functions of caspases
Cellular mechanisms controlling caspase activation and function.
Cellular regulation of ribonucleotide reductase in eukaryotes.
Akt and p53R2, partners that dictate the progression and invasiveness of cancer. - For those who like more practical applications, this article explores the relationship of the protein of interest of this paper and cancer
The caspase proteins play a vital role in the initiation and execution of apoptosis after cytochrome c has been released. Effector caspases (i.e. - caspase-3 and caspase-7) are responsible for initiating the degradation phase of apoptosis. Previous research has shown that cytochrome c binds Apaf-1 forming the apoptosome, which then activates caspase-9. Caspase-9, once activated, can then directly cleave and activate caspase-3 and caspase-7.
The Brentnall research team focused their study on defining the individual functions of caspase-3, caspase-7 and caspase-9 in the cell death process. They were able to obtain results by genetically manipulating cell lines during intrinsic cell death simulations. In doing so they found that caspase-3 can inhibit reactive oxygen species (ROS) production and is the primary executer of apoptosis. Caspase-7 is responsible for ROS production and cell detachment. Finally, caspase-9 can remodel mitochondria and increase ROS production by cleaving Bid into tBid.
Although it was previously believed that these caspase proteins acted downstream of the cytochrome c release, these results show that not only do they have effects on mitochondria, but they also function upstream of intrinsic apoptosis. The effects are mostly seen within the electron transport chain wherein these caspases mediate the transport of electrons from complex III to complex IV. Facilitating the cellís energy production is vital to cell survival, thus when these caspases are activated, the cell cannot produce energy and subsequently dies. The data collected in this study suggest that there may be a feedback loop involved where these caspases function that helps regulate their activity.
Links related to the paper:
Caspase-9 and effector caspases have sequential and distinct effects on mitochondria
Caspase functions in cell death and disease - Follow this link for an amended figure 1:
Cellular mechanisms controlling caspase activation and function
The role of individual caspases in cell death induction by taxanes in breast cancer cells
Caspases and apoptosis - This text provides basic background information about apoptosis and caspases.
In the nematode Caenorhabditis elegans, the AVG interneuron spans the anteroposterior body axis of the organism. The Wnt signaling pathway is a widely conserved pathway that upregulates gene expression in its canonical form. Secreted Wnt ligands serve a role in the polarization and orientation of neurons during C. elegans development. Therefore, precise control of Wnt pathway activation is necessary for wild type nervous system formation.
Moffat et al. demonstrate that correct polarization and positioning of the AVG interneuron is mediated by transmembrane RING finger protein PLR-1. PLR-1 suppresses the binding of Wnt ligands CWN-1 and CWN-2 by lowering the number of Frizzled (Frz) receptors located on the exterior of the AVG cell membrane. PLR-1 ubiquitylates an invariant lysine in Frz-like receptors and internalizes them into endosomes, which are membrane bound compartments in the interior of the cell. This renders them unavailable to respond to a Wnt signal. Additionally, PLR-1 lowers cell surface concentrations of receptor tyrosine kinases Ror and Ryk that also function as Wnt receptors or co-receptors with Frz.
The lack of PLR-1 expression in AVG results in anteroposterior polarity defects in the neuron. This is a consequence of overexpression of Frz MOM-5 receptors, leading to uninhibited activation of the Wnt pathway by CWN-1 and CWN-2 ligands. In mutants with ectopic PLR-1 expression, anteroposterior polarity inversion of ALM and PLM mechanosensory neurons is observed. Therefore, Moffat et al. demonstrate the role of Wnt signaling in C. elegans neuronal development and highlight a mechanism for regulation via the internalization of receptor proteins.
Links related to the paper:
The ubiquitin code and its decoding machinery in the endocytic pathway
A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans
RING Finger Proteins: Mediators of Ubiquitin Ligase Activity
Canonical Wnt signaling is a well studied signaling pathway that plays an important role in regulating gene transcription, particularly in the case of axial patterning regulation. This pathway can itself be regulated by balancing with another well-studied signaling pathway: Sonic hedgehog (Shh). While multiple experiments have been conducted to show the mutually antagonistic relationship between Wnt and Shh during dorsal-ventral patterning of the nervous system, the mechanisms by which this process occurs are not yet fully understood.
This experiment focused on studying the ventral anterior homeobox (Vax) transcription factors that are induced by Shh and assessing these inductive effects. It was discovered that the Vax2 transcription factor binds to the 5th intron region of the Tcf712 gene, which is a key mediator of the Wnt signaling pathway. The intron region that Vax2 binds to is significant because of its extraordinarily high conservation across vertebrate evolution. For example, the nucleotide sequence of this region displays 99.2% percent identity between humans and chickens.
One of the characteristics of the this region that stood out was that the subsequent mRNAs of this transcribed DNA region were found exclusively in the head region of developing embryos. The subsequent protein translated from this mRNA (dnTcf712) is truncated and because of this can no longer bind to β-catenin and instead binds to corepressor proteins such as Groucho (Grg). Because β-catenin can no longer be activated, the Wnt signaling pathway is ultimately inhibited.
Studies conducted to support this proposed mechanism include induced mutations of Vax2 in mice that let to a loss of ventral neural retina in mice. Similarly, elimination of dnTcf712 via induced mutation of XTcf712 in Xenopus laevis resulted in headless embryos. Experimental results such as these support the notion idea that even perfectly canonical Wnt signaling can be inhibited by a Shh induced, Vax activated dnTcf712 protein from outside the Wnt pathway. The relationship between Shh and Wnt interactions in developing model organisms are not only important in improving our understanding of nervous system development in vertebrates, but also how these signaling pathways operate in adult tissues and cancer, especially due to the high conservation of these genes across vertebrate species.
Links related to the paper:
Autoregulation of canonical Wnt signaling controls midbrain development
Hedgehog-regulated localization of Vax2 controls eye development
A homeobox gene, vax2, controls the patterning of the eye dorsoventral axis
Spatial and temporal regulation of Wnt/β-catenin signaling is essential for development
In the Drosophila embryo, patterning of the dorsoventral axis is dependent on a ventral to dorsal concentration gradient of the Dorsal gene (Dl). Dl activates mesoderm-determining genes, such as twist and snail (sna), and represses dorsal determining genes, such as decapentaplegic (dpp) and zerknuilt (zen). Torso mediated RTK signaling disturbs the Dl gradient by downregulating genes Capicua (Cic) and Groucho (Gro) which represses zen and dpp. The Torso pathway also induces genes that repress sna transcription, such as huckbein (hkb). This experiment is to show how the Torso pathway influences the Dl gradient through the wnt inhibitor of Dorsal (wntD).
They used 5 wild type, Dsor, tor, and wntD mutant embryos immunostained for Sna, Vnd, and Brk or hybridized for sog and wnt D
Torso mediated RTK signaling was found to exclude the expression of Sna, Vnd, Brk, and sog. Torso reduces levels of nuclear Dl and induces the expression of wntD, which was found to reduce Dl target gene expression.
Links related to the paper:
Drosophila blastoderm patterning
The regulation and functions of MAPK pathways in Drosophila
Spatial and temporal organization of signaling pathways
The Capicua repressor - a general sensor of RTK signaling in development and disease
Diabetes mellitus, a metabolic disease identified in patients with high blood glucose levels and deficiencies of insulin production or response, affects over 9% of people in the US today. Strong evidence has demonstrated that certain cancers are associated with the diabetic population, though little is known of the mechanisms linking the two.
Thought to be caused by insulin growth factor 1 signaling in diabetics, an alternative theory relating diabetes to the development of cancerous tissue involves high glucose levels having an effect on the Wnt/β-catenin signaling pathway. Previously unknown, Chocarro-Calvo et al. demonstrate that elevated glucose levels promote the nuclear localization of β-catenin in multiple human tumor-derived cell lines. Mechanistically, the study found that glucose mediates the formation of a β-cat/T cell factor via the promotion of β-cat acetylation which in turn promotes nuclear localization and transcriptional factors.
Increased nuclear accumulation of β-catenin in response to high glucose was demonstrated in colon, ovary, breast and enteroendocrine human cell lines, suggesting that deregulation of the Wnt pathway through metabolic targets such as glucose have large implications in anticancer therapeutics. The results of this study illuminate a mechanism to begin to explain the association between diabetes and certain cancers.
Links related to the paper:
Diabetes Mellitus and Cancer Risk in a Network of Case-Control Studies
WNT/β-catenin increases the production of incretins by entero-endocrine cells
Nuclear localization of β-catenin by interaction with transcription factor LEF-1
Wnt/β-Catenin Signaling in Development and Disease