Through activation of NRF2 by direct interaction, HER2 confers drug resistance of human breast cancer cells

Research from Hyo Jin Kang and Yong Weon Yi,etc. shows that HER2 confers drug resistance of human breast cancer cells through activation of NRF2 by direct interaction.


Taken together, the results of their research suggest that active HER2 (HER2CA) binds to NRF2 to activate the transcription of a set of genes which are involved in drug resistance of cancer cells at multiple levels. Various studies have demonstrated that HER2 or NRF2, independently, gives resistance of cancer cells to a range of therapeutics. However, no direct link, between HER2 and NRF2 in drug resistance of cancer cells, has ever been reported. In the present study, they first demonstrated the direct link between HER2 and NRF2 in drug resistance of cancer cells. Their present study suggests that HER2 may regulate NRF2 stability and/or activity through direct physical interaction. This HER2-NRF2 interaction may contribute to 1) stabilization of NRF2 by inhibiting or competing with KEAP1 similar to other proteins as previously reported. Data presented in this study support this possibility: 1) the expression of FLAG-NRF2 protein was increased in HER2CA-transfected MCF7 and HEK293T cells and a GFP-tag, which inhibits polyubiquitination-dependent proteasomal degradation, increased NRF2 protein expression in HEK293T cells even in the absence of HER2CA expression; 2) enhancing translocation of NRF2 into nucleus; or 3) recruitment of HER2, as a coactivator, to the promoters of NRF2-target genes. In fact, it has been reported that HER2 is localized in the nucleus of cells to act as a transcriptional activator. Further studies are needed to determine the exact roles of HER2-NRF2 interaction in regulation of drug resistance in HER2-amplified or -activated human cancer cells.


HER2 confers drug resistance of human breast cancer cells through activation of NRF2 by direct interaction, Scientific Reports 4, Article number: 7201︱doi:10.1038/srep07201

Prion protein- and cardiac troponin T-marked interstitial cells develop into beating cardiomyocytes from the adult myocardium spontaneously

A recent study from Mariko Omatsu-Kanbe, Yuka Nishino and Nozomi Nozuchi,etc. shows that prion protein- and cardiac troponin T-marked interstitial cells from the adult myocardium  spontaneously develop into beating cardiomyocytes.


Evidence from their research showing that the number of beating ACMs reaches a plateau in adulthood in the postnatal mouse heart and that PrP+cTnT+ cells are detected in human heart tissues derived from patients over 80 years of age suggests that native ACMs stay in the heart until advanced stages, without appreciably differentiating into normal cardiomyocytes, under physiological conditions. They usually counted ~500 beating ACMs per heart after several days of culture, which is thought to be lower than the actual number of ACMs resident in the heart. This underestimation of the cell number may due to the loss of a number of native ACMs following repeated centrifugation during the isolation procedure, as the isolated ventricular fraction contains heterogeneous small cells, including native ACMs, co-precipitated with cardiomyocytes, and/or to the reduced ability to develop into beating cells during the preparation procedures.

It is expected that the quiescence of native ACMs under physiological conditions makes it possible for these cells to stay within the normal heart highly organized to generate rhythmic impulses to induce rhythmic contractions of cardiomyocytes. On the other hand, ACMs preserve their ability to develop into beating cells under culture conditions, even immature and incomplete cardiomyocytes. It may therefore be possible in the future to identify certain culture conditions to develop native ACMs into more mature cardiomyocytes following the complete isolation of these cells.

The trigger of starting the spontaneous development of native ACMs into beating cells remains unclear, at least with respect to the isolation of the cells and culture under three-dimensional conditions using methylcellulose-based semisolid culture medium. In the present and previous studies, they found that sufficient isolation of native ACMs from neighboring ventricular myocytes is required to yield beating cells in culture, and, indeed, insufficient enzymatic digestion results in the failure to obtain beating ACMs from the mouse heart. In the normal mouse or human heart, PrP+cTnT+ native ACMs were usually observed as solitary or clustered cells, but not multinucleated cells. These observations also suggest that the fusion or multinucleation of ACMs occurs after the isolation procedures. These data may lead to the view that the independence of native ACMs from the microenvironments due to the death of the neighboring ventricular myocytes stimulates the spontaneous development of these cells into beating cardiomyocytes under pathophysiological conditions. It would be of interest to explore the nature of ACMs in infarct areas and/or border zones in which adjacent cardiomyocytes die in diseased human hearts in the future study.

Their findings are thus considered to provide a view concerning the presence of quiescent but still functionally viable cells in the normal adult organ that originate from the fetal stage tissues.


Prion protein- and cardiac troponin T-marked interstitial cells from the adult myocardium spontaneously develop into beating cardiomyocytes, Scientific Reports 4,Article number: 730︱doi:10.1038/srep07301

Discovery of turning stem cells into killing machines to fight brain cancer

Published in the journal Stem Cells, this study was the work of scientists from Massachusetts General Hospital and the Harvard Stem Cell Institute. Stem cells were engineered genetically to produce and secrete toxins which kill brain tumours in experiments on mice, without killing normal cells or themselves. To test the procedure in humans is its next stage. They had been researching a stem-cell-based therapy for cancer, which would kill only tumour cells and no others for many years. They used genetic engineering to make stem cells that spewed out cancer-killing toxins, however, they were also able to resist the effects of the poison they produced. Moreover, they posed no risk to normal and healthy cells. The stem cells were surrounded in gel and placed at the site of the brain tumour in animal tests after it had been removed. Their cancer cells then died because of no defense against the toxins.


Toxin-producing stem cells which are in blue color help kill brain tumour cells in the tumour cavity in green color. lead author and director of the molecular neurotherapy and imaging lab said the results were very positive. He also said that cancer-killing toxins have been used with great success in the variety of blood cancers, but they don’t work as well in solid tumours because the cancers aren’t as accessible and the toxins have a short half-life. It shows you can attack solid tumours by putting mini pharmacies inside the patient which deliver the toxic payload direct to the tumour. But so far the technique has only been tested in mice and on cancer cells in the lab, so much more work will need to be done before scientists will know if it could help patients with brain tumours. She said this type of research could help boost survival rates and bring much-needed progress for brain cancers with the hopes that therapies could be used in clinical trials within the next five years.

Speed Cancer Drug Discovery by Analyzing Fleeting Protein-Protein Interactions

Salk scientists have developed a versatile platform that allows to detect low-affinity and transient protein-protein interactions in living cells in real time. This approach, published in Cell Reports, would dramatically accelerate the identification of many potential new drug targets and provide an immediate platform to screen for badly needed new drug candidates that disrupt abnormal protein interactions.


As known in the biomedical circle, the number of protein interactions that are currently targeted by drugs is incredibly small compared to the total number of protein interactions that could be targeted for therapeutic benefit. It will be of massive breakthrough that scientists can crack the nut of screening for drugs that disrupt cancer-relevant protein interactions, with implications for many diseases including cancer.

Scientists attempt to visualize these brief and transient interactions between proteins via using a molecule called luciferase, an enzyme that generates bioluminescence. They adapted an old method in which luciferase is split in half, and then attached each half to two proteins of interest. During the proteins associate, luciferase’s two halves are brought together and emit light.

ReBiL as a enhanced tool

The secret to the new method comes in the many tweaks and improvements, which is symbolized by the acronym applying to the method — ReBiL — which indicates “recombinase enhanced bi-molecular luciferase complementation.”

To test the approach, investigators applied it to the interaction between two proteins, Ube2t and FANCL, that had never been seen in living mammalian cells. These proteins involved in the cell’s ability to detect and repair DNA damage, a function that is often disrupted in diseases. The ability of ReBiL to reveal the stealthy FANCL-Ube2t reaction suggested the method could be a powerful technique for observing other similarly challenging interactions.

The Salk scientists then used ReBiL to study a promising target for cancer, the interaction between the proteins p53 and Mdm2. The function of p53 is affected in almost all cancers and, in many cancers, too much Mdm2 prevents p53 from functioning properly. Hence, a major goal of cancer scientists has been to develop drugs that prevent Mdm2 from binding to p53, and to thereby activate p53 to kill the tumor cell.

Additionally, the scientists used ReBiL to confirm that some drugs work as expected to prevent Mdm2 from binding to p53. On the other hand, when they applied this new method to a new class of promising drugs called stapled peptides, they found that the drugs had difficulty entering cells and had the unexpected and unintended ability to kill cells by punching holes in their protective membrane. ReBiL provides a fast and simple way to try to improve stapled peptides to enable them to get into the cell, bind to their targets and kill cells by the specific route they were designed to use.


A Versatile Platform to Analyze Low-Affinity and Transient Protein-Protein Interactions in Living Cells in Real Time. Cell Reports, 2014


Combination Therapies Drastically Shrinks the Deadly Form of Brain Cancer

A new study, published in the journal Molecular Cancer Therapies, reports that when combined with radiation treatment, marijuana can effectively shrink one of the most aggressive types of brain tumors. And previous researches has revealed that cannabis can both destroy certain cancer cells and reduce the growth of others.


Investigators outlined the dramatic reductions in high-grade masses, when treated with a combination of radiation and two different marijuana compounds. In many cases, those tumors shrunk to as low as one-tenth the sizes of those in the control group, showing that the combination therapies are promising in treating the form of aggressive cancer.

Additionally, the scientific team is the first to document its effect of marijuana on the disease when used alongside radiation. The results from the study showed that the final effect was superior to the sum of the parts, supporting calls for formal trials in human to test these combination.

The team examined mice that had been infected with glioma and subsequently treated with radiation alone or in combination with varying levels of two cannabis compounds: THC and CBD. They found that the tumors were best treated by low doses of both THC and CBD that made the tumors more receptive to radiation treatment.

They also found that together, the low doses of THC and CBD produced a similar effect to a large dose of either compound, which is noteworthy because it indicates that patients may ultimately experience fewer side effects.


The Combination of Cannabidiol and Δ9-Tetrahydrocannabinol Enhances the Anticancer Effects of Radiation in an Orthotopic Murine Glioma Model. Molecular Cancer Therapies, November 14, 2014

A New Drug Change The Human Tumor Metabolite

The Manchester scientists found a new drug, and the new drug can inhibit the tumor growth. The new drug, together with the radiation therapy, could be applied for effective treatment of tumor in the clinical.

In the process of tumor cell metabolism, the lactic acid was produced. The Lactic acid cause toxicity to tumor cells, so the lactic acid must be transferred by the molecular transporters (MCT) out of tumor cells. Astrazeneca pharmaceutical drug-AZD3965 inhibited a MCT1 in lung cancer cells. Researchers of the Manchester investigated the therapeutic effect of the drug combined with radiotherapy. The further study confirmed that the new drug, together with the radiation therapy, could be applied for effective treatment of tumor in the clinical.

Professor Ian Stratford said AZD3965 can inhibit MCT1, specifically targeting tumor by tumor metabolism. This drug was used as a single drug test in clinical trials. And he has shown that the drug combined with radiotherapy could be the new treatment of cancer patients.


Inhibition of Monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport [J]. Mol Cancer Ther, 2014; 13(12): 1-12.

Metabolic Reprogramming Induces Regression of Specific Tumors

Researchers from University of Texas MD Anderson cancer center have indicated that altering tumor suppressor gene p53 family members may induce rapid regression of tumors lack of p53. This study was published in Nature.

TP53 is commonly altered in human cancer and the Tp53 reactivation suppresses tumors in vivo in mice (TP53 and Tp53 are also known as p53). This strategy has proven difficult to implement therapeutically.


In this study, scientists try to examine an alternative strategy by manipulating the p53 family members, Tp63 and Tp73 (also known as p63 and p73). The acidic transactivation-domain bearing (TA) isoforms of p63 and p73 structurally and functionally resemble p53, whereas the δN isoforms of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53, TAp63 and TAp73 to inhibit their tumour-supressive functions. The researchers have shown that the deletion of δN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumours through upregualtion of IAPP, the gene that encodes amylin.

In addition, they found that IAPP is causally involved in this tumor regression and that amylin functions through the calcitonin receptor (CalcR) and receptor activity modifying protein 3 (RAMP3) to inhibit glycolysis and induce reactive oxygen species and apoptosis.

This study provides new insight of targeting tumors which are lack of p53 or with p53 mutation. Meanwhile, the researchers also identify the key receptors of cancer cells which are eliminated of p53 gene. These receptors may be potential prognostic markers to ensure if pramlintide will be effective to cure the patients with p53 mutation or lack of p53.


Venkatanarayan A, Raulji P, Norton W, et al. IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo[J]. Nature, 2014.

How Hedgehog Signaling Pathway Induces Breast Cancer Metastasis

Scientists from University of Texas MD Anderson cancer center have revealed that , a unique cell signaling pathway hedgehog, may be the mechanism behind breast cancer metastasis. The study was published in Cell.

Emerging evidence has purported long noncoding RNA (IncRNA) as a new class of players involved in the development and progression of cancer. However, the regulatory roles played by IncRNA in breast-cancer-associated aberrant signaling pathways/transcriptional programs are not completely understood.


In this study, researchers have reported a role for INcRNA BCAR4 in breast cancer metastasis that is mediated by chemokine-induced binding of BCAR4 to two transcription factors with extended regulatory consequences. BCAR4 binding of SNIP and PNUTS in response to CCL21 releases the SNIP1′s inhibition of p300-denpendent histone acetylation, which in turn enables the BCAR4-recruited PNUTS to bind H3K18ac and relieve inhibition of RNA pol Ⅱ via actication of the PP1 phosphatase. This mechanism activates a noncanonical Hedgehog/GLI2 transcriptional program that promotes cell migration. BCAR4 expression correlates with advanced breast cancers, and therapeutic delivery of locked nucleic acids (LNAs) targeting BCAR4 strongly suppresses breast cancer metastasis in mouse models.

Their finding have provided supporting evidence for the regulatory roles played by IncRNA in the progression of aggressive breast cancers. Broadly, the results of the therapeutic effectiveness breast cancer metastasis document an example showing the pharmacologic value of INcRNA in human cancer and other diseases.


Xing Z, Lin A, Li C, et al. lncRNA Directs Cooperative Epigenetic Regulation Downstream of Chemokine Signals[J]. Cell, 2014.

Endocan is as a potential diagnostic or prognostic biomarker for chronic kidney disease

A recent study shows that endocan is as a potential diagnostic or prognostic biomarker for chronic kidney disease.

In the study by Yilmaz et al., there are some limitations. They have performed just a single measurement of serum endocan. A single point measurement of serum endocan is a little relevant, but serial multiple measurements could give more information on prognostic outcome of CKD. For instance, Li and Wang et al. performed multiple point measurements of serum endocan level during evaluation of acute rejection after renal transplantation. Multiple measurement of serum endocan level could discriminate acute rejection from renal allograft dysfunction. They additionally showed that endocan expression was located mainly in glomeruli, which may give a clue to the origin of serum endocan in CKD patients. Another instance is a report on serum endocan levels in septic patients. The severity of sepsis showed positive correlation with initial serum endocan levels. Moreover, it was significantly increased in non-survivors.


However, the lack of multiple follow-up data on serum endocan levels prohibits the evaluation of sepsis treatment outcome, which requires multiple measurements. Another limitation is that Yilmaz et al.did not rule out accompanying cancers or other inflammatory diseases, which could be sources of serum endocan. Serum endocan is detected as a few hundred picograms in 1 ml of serum under normal physiologic conditions. Serum endocan solely could not inform regarding the location or kinds of diseases, but its detection over the normal range may give a clue to search for some diseases, such as systemic inflammatory diseases, cardiovascular diseases, and various cancers. Finally, it is unclear whether the increased serum endocan level in CKD patients was the result of an increased secretion or a decreased renal clearance. The clearance mechanism of endocan has not yet been identified. As renal function declines, serum endocan level increases, which may be due to increased production or decreased clearance. The former might be due to kidney inflammation, which is preferable. In this report, serum endocan levels of patients in the third quartile (6.6 ng/ml) or fourth quartile (13.3 ng/ml) in the CKD classification based on estimated glomerular filtration rate were significantly higher than those of patients in the first (1.2 ng/ml) and second quartiles (2.8 ng/ml). This pattern was the same for high-sensitivity C-reactive protein, which was induced considerably by kidney inflammation. However, the reason why serum endocan levels were significantly higher in CKD than in any other disease conditions must be evaluated. The possibility that the increased serum endocan levels in CKD patients resulted from decreased clearance could be evaluated simply by urine endocan level. Serial follow-up of serum endocan levels in CKD patients could also be informative in this regard.

In conclusion, Yilmaz et al. have reported an endocan as a novel prediction marker of all-cause mortality and cardiovascular events in CKD patients. More detailed study of molecular mechanisms in endocan expression and degradation in CKD may increase the value of serum endocan levels.


Endocan as a potential diagnostic or prognostic biomarker for chronic kidney disease, Kidney International (2014) 86, 1079–1081; doi:10.1038/ki.2014.292

Silence KRAS using siRNA to kill cancer cell

Recently, researchers have developed a new approach to block the KRAS oncogene, one of the most frequently mutated genes in human cancer. The approach relies upon siRNA to attack KRAS, which is tantalizing yet elusive target for drug developers.


The findings, published in the journal Molecular Cancer Therapeutics, show that using a form of siRNA to halt KRAS not only dramatically stunted the growth of lung and colon cancers in cultured cells and mice but also blocked metastasis.

As known in the biomedical circle, KRAS is a signaling molecule — a protein switch that triggers a cascade of molecular events that tell cells to grow and survive. Mutations in the KRAS gene create a switch that is perpetually “on,” causing cells to divide uncontrollably. KRAS mutations are present in approximately 30% of human cancers, particularly lung, colon, pancreatic, and thyroid cancer.

Over the past decades, KRAS has been widely regarded as undruggable target, since it lacks good pockets or binding sites for small molecules and drug to bind to. Some researchers have tried instead to target the proteins downstream in the KRAS signaling cascade, but those attempts have also had limited success.

Instead of other conventional methods, a new genetic tool known as RNA interference (also called RNAi) is employed to destroy the KRAS protein before it fully forms. RNAi uses bits of synthetically engineered RNA to silence specific genes. These bits of RNA bind to specific genetic messages called mRNA in the cell and direct enzymes to recognize the messages as enemies. In this context, the enzymes destroyed the genetic messages of KRAS mRNA so that KRAS can’t be made. As a result, the cells don’t grow, replicate, or move nearly as well.

RNAi has shown great promise in the treatment of liver diseases, viral infections, and cancers. To see if this approach could thwart the KRAS oncogene, researchers had to test different sequences of RNA to determine which one most effectively tagged KRAS for destruction. Of five RNA sequences, the researchers identified two candidates worthy to take into cancer models.

When they delivered these sequences into tissue culture cells, they found that the siRNAs destroyed over 90% of the KRAS gene messages, significantly impairing the growth of cancer cell lines. The siRNA sequences will have to be designed to specifically target the mutant form of KRAS without disrupting the normal form of the gene, which is necessary for maintaining normal growth in healthy cells.


Therapeutic Silencing of KRAS using Systemically Delivered siRNAs. Molecular Cancer Therapeutics, 2014

Cancer related signaling pathway, e.g. Wnt signaling,stat3,NF-KB