The latest studies establish a novel pathway through which Sem7a and its receptors regulate Chi3l1, revealing a host axis involving IL13Rα2 that plays a critical role in generating a pulmonary microenvironment that is critical to license metastasis.

The prototypic chitinase-like protein Chi3l1 is induced in cancers and portends a poor prognosis, but whether it contributes to cancer progression is unknown. To address this gap in knowledge, the scientists investigated the production of Chi3l1 in melanoma lung metastases. The study found that Chi3l1 was induced during pulmonary melanoma metastasis and that this induction was regulated by the semaphorin Sema7a, interacting in stimulatory or inhibitory ways with its β1 integrin or Plexin C1 receptors, respectively. In mouse strains with genetic deletions of Chi3l1 or Sema7a, there was a significant reduction in pulmonary metastasis. Notably, antiserum raised against Chi3l1 or Sema7a phenocopied the reduction produced by genetic deletions. Melanoma lung metastasis was also decreased in the absence of IL13Rα2, a recently identified receptor for Chi3l1, consistent with a key role for Chi3l1 in melanoma spread. The study confirmed roles for Sema7a and Chi3l1 in pulmonary metastasis of EMT6 breast cancer cells.

Taken together, the studies establish a novel pathway through which Sem7a and its receptors regulate Chi3l1, revealing a host axis involving IL13Rα2 that plays a critical role in generating a pulmonary microenvironment that is critical to license metastasis.

Reference:

Bing Ma, Erica L. Herzog,et al.Role of Chitinase 3–like-1 and Semaphorin 7a in Pulmonary Melanoma Metastasis [J].Cancer Res; 75(3); 1–10.

TDP-43 is an RNA-binding protein and a biomarker of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration.  Here, we identify lysine acetylation as a novel post-translational modification controlling TDP-43 function and aggregation.

From a large scale identification of acetylation sites data (a global proteome contain 1,750 proteins), we found two acetylation sites (Lys-145 and Lys-192) on TDP-43. And then, confirmed the modification by pan-acetylation antibody and mass spectrum.

As TDP-43 binds to 6,000 genes and regulates target RNAs that are essential for proper neuronal development and synaptic function, given that the acetylated lysines are located within the RRM domains, we guess the acetylation may affect its RNA binding activity. The double mutant (TDP-K145Q or TDP-2KQ), showed a 50–65% decrease in RNA binding. TDP-43 acetylation mimics (K-Q) to the cytoplasm increased P-409/410 levels in insoluble fractions.

Co-expression of WT HDAC6, but not a catalytically inactive H803A mutant, together with CBP was sufficient to deacetylate cytoplasmic TDP-43 under normal cellular conditions.

We also show acetylated TDP-43 lesions are found in ALS patient spinal cord, indicating that aberrant TDP-43 acetylation and loss of RNA binding.

The identification of a reversible TDP-43 acetylation switch provides a novel framework to understand both physiological and pathological TDP-43 functions, which could lead to targeted therapies against ALS.

Scientists from University of Manchester have demonstrated that how proteins were cut in lung cancer cells, making metastasis possible. Their finding may be helpful in the development of cancer therapy to block metastasis in the future. This study was published in Cell Reports.

Metastasis, a multistep process beginning with local invasion and culminating in the colonization of distant organs by cancer cells, is responsible for more than 90% of all cancer deaths. Metastasis of arcinoma cells often commences with the disassembly of junctional complexes and downregulation of other epithelial traits coupled with the acquisition of migratory and invasive mesenchymal phenotype(epithelial-mesenchymal thransition[EMT]).

In this study, researchers show that in response to human grow factor(HGF), HUWE1(WWE domain-containing protein 1) ubiquitylates TIAM1(metastasis inducing protein 1) on lysine 595, triggering its proteasomal degradation predominantly at cell-cell adhesions, thereby enabling disassembly of cell junctions and induction of cell migration and invasion, including in lung carcinoma cells. They also show that TIAM1 and HUWE1 protein levels are negatively correlat3ed in early-stage lung cancer specimens, consistent with this regulatory mechanism operating in human tumors.

Reference:

Vaughan L, Tan C T, Chapman A, et al. HUWE1 Ubiquitylates and Degrades the RAC Activator TIAM1 Promoting Cell-Cell Adhesion Disassembly, Migration, and Invasion[J]. Cell Reports, 2014.

Scientists from Case Western Reserve University have developed a new therapeutic method to weaken and kill cancer cells. This technique could enhance the level of cancer-inhibiting protein to kill tumors by directly targeting cancer cells. This study was published in PNAS.

Prompt response to double-strand break(DSB) caused by, for example, ionization radiation(IR), requires sequential and coordinated assembly of DNA damage response(DDR) proteins at damage sites. Recent research findings reveal key roles of the tumor suppressor p53-binding protein 1(53BP1) and BRCA1 in the decision making of DSB repair.

DSB repair sits at the core of genome stability maintenance. Abnormalities in the repair pathway often lead to the development of cancers and resistance to anti-cancer therapies. Tumor suppressor p53-binding protein 1(53BP1), a protein critical in regulating DSB repair, is reduced in advanced breast tumors. Furthermore, low levels of 53BP1 correlated with poor prognosis and resistance to chemotherapy. Thus, the protein level of 53BP1 is important for therapeutic response. However, mechanisms regulating 53BP1 protein levels are poorly understood.

In this study, researchers report a previously unidentified mechanism regulating the protein level of 53BP1, specifically, ubiquitin-conjugating enzyme H7(UbcH7)-dependent ubiquitination and proteasome-dependent degradation. They further propose an innovative hypothesis that increasing the protein level of 53BP1 enhances the effect of radiotherapy or chemotherapy through suppressing faithful DSB repair.

Reference:

Han X, Zhang L, Chung J, et al. UbcH7 regulates 53BP1 stability and DSB repair[J]. Proceedings of the National Academy of Sciences, 2014, 111(49): 17456-17461.

Research from University College London and Kings College London claims that falling rates of smoking, better diagnosis, and more advanced technology have led to a one percent decline in the number of cancer deaths since 1990. The researchers have called it a “special point in history” which could eradicate cancer related mortality “during the course of the coming 20-30 years.”

However, researchers warn that cutbacks to NHS cancer services could damage this trend, especially after NHS England announced that 25 life extending treatments would no longer be available on the Cancer Drugs Fund. In the report titled ‘Overcoming Cancer in the 21st Century,’ David Taylor, emeritus professor of pharmaceutical and public health policy at UCL, said the British economy would be damaged if adequate cancer treatments were cut.

“What makes this a special point in history, is that cancers are in the process of becoming either preventable or effectively curable,” he said. “There should be no question of the NHS not being able to afford world-class cancer prevention and treatment – no health service user should feel they have to beg for the best possible therapies.”

While the scientists warned there will be no “magic bullet” for patients in the near future, they added that advances in genetic research would also lead to better development of cancer drugs, as well as earlier detection of cancer symptoms.“

In the first half of the 20th century the big gains were infectious disease…the second half has been drops in vascular disease death rates,” he said. “The next great surge will be in cancer-related death reduction. We’ve already done reasonably well. We can do much better. We shouldn’t chicken out on it,” Taylor added.“What we probably need is an ‘Innovative Drugs Fund’ that covers all low-volume, high-unit cost drugs and probably needs to be separately funded. The scope of the Cancer Drugs Fund isn’t wide enough.

”Last week, NHS officials criticized the Cancer Drugs Fund, calling it the “most poorly thought through pieces of health public policy,” and stating that it is not cost efficient. The fund was created by the coalition government to select the most effective cancer drugs to supply to the NHS.While Prime Minister David Cameron budgeted the fund at around £200 million in 2011, it is estimated that it will actually cost around £1.16 billion by 2016.

In a recent study appearing in the journal Cancer Discovery, a research team have targeted telomeres with a small molecule called 6-thiodG that recruits the cell’s “biological clock” to kill cancer cells and shrink tumor block.

To prevent the cancer growth, the 6-thiodG molecule acts by targeting a unique mechanism that is thought to regulate how long cells can stay alive, a type of aging clock. This biological clock is defined by DNA structures known as telomeres, which become shorter every time the cell divides. Once telomeres have shortened to a critical length, the cell would enter into the apoptosis.

A new drug showed promising results

Investigators found that 6-thio-2′-deoxyguanosine could stop the growth of cancer cells in culture and decrease the growth of tumors in mice, and broad efficacy against a range of cancer cell lines with very low concentrations of 6-thiodG, as well as tumor burden shrinkage, appeared in the tested mice.

The successfully developed drugs can block telomerase, an RNA protein complex which makes telomeres in the adequate length, to trigger cell death and shrink tumor. The outcome occurrence after administering for long periods is partially because cells in any one tumor have chromosomes with different telomere lengths and any one cell’s telomeres must be critically shortened to induce death.

6-thiodG is preferentially used as a substrate by telomerase and disrupts the normal way cells maintain telomere length. Because 6-thiodG is not normally used in telomeres, the presence of the compound acts as an ‘alarm’ signal that is recognized by the cell as damage. As a result, the cell stops dividing and dies.

As known in the biomedical circle, telomerase is an almost universal oncology target, yet there are few telomerase-directed therapies in human clinical trials. To be remarkably encouraging, 6-thiodG potentially lead to positive effectiveness with minimal side effects in the blood, liver and kidneys of the mice that were treated with the molecule.

Reference:

Induction of Telomere Dysfunction Mediated by the Telomerase Substrate Precursor 6-Thio-2′-Deoxyguanosine. Cancer Discovery, 2014.

Recently, the article published on the Cancer Discovery demonstrated that 6-thio-dG may provide a new telomere addressed telomerase-dependent anticancer approach.

Telomerase is an almost universal oncology target, yet there are few telomerase directed therapies in human clinical trials. The relationships between telomerase and telomeres represent attractive targets for new anticancer agents. The research report that the nucleoside analogue 6-thio-2’-deoxyguanosine (6-thio-dG) is recognized by telomerase and is incorporated into de novo–synthesized telomeres. This results in modified telomeres, leading to telomere dysfunction, but only in cells expressing telomerase. 6-Thio-dG, but not 6-thioguanine, induced telomere dysfunction in telomerase-positive human cancer cells and hTERT-expressing human fibroblasts, but not in telomerase-negative cells. Treatment with 6-thio-dG resulted in rapid cell death for the vast majority of the cancer cell lines tested, whereas normal human fibroblasts and human colonic epithelial cells were largely unaffected. In A549 lung cancer cell–based mouse xenograft studies, 6-thio-dG caused a decrease in the tumor growth rate superior to that observed with 6-thioguanine treatment. In addition, 6-thio-dG increased telomere dysfunction in tumor cells in vivo. These results indicate that 6-thio-dG may provide a new telomereaddressed telomerase-dependent anticancer approach.

Reference:

Maria Romina Girotti, Filipa Lopes, et al. Induction of Telomere Dysfunction Mediated by the Telomerase Substrate Precursor 6-Thio-2’-Deoxyguanosine[J].Cancer Discovery, 2014.10.1158/2159-8290.

Scientists from University of California, Davis have demonstrated the complex relationship between Rbm38 and p53, indicating how organism calibrates p53 level. This finding was published in PNAS.

RNA-binding motif protein 38(Rbm38) is a target of the p53 family and modulates p53 expression via mRNA translation. The biological function of Rbm38 is implicated in the cell cycle control, differentiation, and senescence. Consistently, altered expression of Rbm38 is found in many types of cancers. For example, Rbm38 overexpression is found in breast cancer patients with poor prognosis and is associated with malignant transformation of colorectal adenoma to carcinoma.

However, the biological function of Rbm38 and the role of the p53-Rbm38 loop in tumor suppression have not been studied in vivo.

In this study, researchers show that mice deficient in Rbm38 exhibit hematopoietic defects and are susceptible to spontaneous tumors and accelerated aging. Furthermore, they show that Rbm38 is critical for p53-mediated radiosensitivity and tumor suppression. Together, their results suggest that Rbm38 is necessary for normal hematopoiesis and for suppressing accelerated aging and tumorigenesis. In addition, the p53-Rbm38 axis might be explored for extending longevity and for tumor suppression.

Reference:

Zhang J, Xu E, Ren C, et al. Mice deficient in Rbm38, a target of the p53 family, are susceptible to accelerated aging and spontaneous tumors[J]. Proceedings of the National Academy of Sciences, 2014, 111(52): 18637-18642.

Researchers from Mayo Clinic have found the first step of the origin of Pancreatic Cancer. Their new finding demonstrates new clues for the tactics of pancreatic cancer prevention. This study was published in Cancer Discovery.

Oncogenic KRAS mutations drive metaplasia of pancreatic acinar cells to a highly proliferative duct-like cell type, which is the precursor for precancerous pancreatic intraepithelial neoplastic (PanIN) lesions. Desmoplasia and an inflammatory environment are defining features of pancreatic cancer. Unclear is how pancreatic cells that undergo oncogenic transformation can cross-talk with immune cells and how this contributes to the development of pancreatic lesions.

In this study, researchers report that oncogenic KRAS mutations in pancreatic acinar cells induce the expression of intercellular adhesion molecule-1(ICAM-1). They show that ICAM-1 can act as a chemoattractant for macrophages. Attracated macrophages release matrix-degrading enzymes, including matrix metalloproteinase 9(MMP9), as well as cytokines such as TNF that synergize with KRAS mutations to drive acinar cell metaplasia. They also demonstrate that depleting marcrophages or neutralizing ICAM-1 in p48^Cre, Kras^G12D-expressing mice dampens the development of precancerous lesions.

In summary, this study for the first time demonstrate that Kras^G12D-expressing acinar cells can expedite their transformation to a duct-like phenotype by inducing local inflammation and macrophage infiltration. They provide a mechanism of how oncogenic Kras mutations and inflammatory microenvironment function synergistically to drive the earliest abnormal pancreatic structures that precede PDA.

Reference:

Liou G Y, Doppler H, Necela B, et al. Mutant Kras-induced expression of ICAM-1 in pancreatic acinar cells causes attraction of macrophages to expedite the formation of precancerous lesions[J]. Cancer discovery, 2014: CD-14-0474.

Suchandrima Saha, Monisankar Ghosh and Samir Kumar Dutta find out a potent tumoricidal co-drug ‘Bet-CA’ – an ester derivative of betulinic acid and dichloroacetate selectively and synergistically kills cancer cells.

 In this study they accentuated the effect Bet-CA deliberates on cancer cells and furthermore the molecular mechanisms by which it induces cell death. It potently inhibits proliferation and induces apoptosis on a wide spectrum of cell lines. Equally importantly, applying discreet yet novel experimental designs they confer Bet-CA spares normal fibroblasts and additional data produced promising evidence for the fact that Bet-CA is purportedly a non toxic compound. Thus, the theme emerging from the studies is that Bet-CA selectively targets the neoplastic cells and impairs their survival and proliferation.

Cellular uptake studies were performed to document the proposed postulation regarding the cleavage of Bet-CA by intracellular esterase. Astoundingly it was noted that Bet-CA being an ester derivative can bypass the barriers of extracellular breakdown, offer itself for cleavage by cellular esterases to present a prominent damage to the malignant variety. Therefore it can be convincingly claimed that Bet-CA is fortuitously endowed with the potential to escape non-specific degradation and synergistically act for benefit.

Suppressed glucose oxidation/glycolysis ratio, mitochondrial hyperpolarization and increased levels of handling stress contribute to the resistance of apoptosis. As cancer cells already have elevated levels of intrinsic ROS it is quite apparent that these malignant cells will become vulnerable when exposed to further oxidative insults. Exposure of cancer cells to subtoxic doses of Bet-CA leads to the significant enhancement of ROS in a temporal fashion. Furthermore, Bet-CA caused no significant generation of ROS in the fibroblastic cell line clarifying the ambiguity and ascertaining the paradigm for the selective killing property of Bet-CA. Of equal importance when cancer cells were challenged with a similar dose of BA, DCA or its stoichiometric mixture and analysed, there was no significant accumulation of intracellular ROS to immediate apoptosis and this phenomenology uncovered suggestively yet another simplifying notion and unequivocally concreted the synergistic potential of Bet-CA.

Cells cannot gain a growth of advantage by losing a mitochondrion and thereby damages inflicted upon it prove to be fatal. True to this fact, Bet-CA confers the degeneration of MMP, opening of MPTP and swelling of the mitochondria. Furthermore, the studies establish that Bet-CA treatment leads to the downregulation of Bcl-xl and activation Bax expression. They have critically determined that Cyt c efflux is followed by apoptosis via the caspase cascade in their experimentations. TUNEL assay documented DNA strand breakage and the phenomenon of apoptosis was further confirmed by dual colour mode flow cytometric analysis. These data are in general agreement with the observation that Bet-CA regulates the expression of apoptosis related proteins, leads to the release of Cyt c and initiates caspase mediated cell death. To detail the granularity for the selective potential of Bet-CA, its effect was studied on the normal cell line. Opposed to the effect Bet-CA poses on the neoplastic cells, there was no alteration in MMP, neither release of Cyt c nor increase in the levels of cleaved caspase-3. Additionally equivalent doses of BA, DCA or BA+DCA (1:1) failed to confer a degradation of ΔΨ_m or the release of Cyt c and observations readout a similar phenomenon straightway pointing the obvious hypothesis for the synergistic potential of Bet-CA. Therefore, what was a rather provocative hypothesis initially, gained a solid basis with ultimate precision factually obviating the selective and synergistic potential of Bet-CA to establish it as the futuristic version of medicine for tackling the nettlesome problems associated with therapy.

In vitro observations enticed them to explore and evaluate whether Bet-CA poses similar barriers to the growth of cancer cells in vivo. Their observations were further corroborated in syngeneic mice melanoma model and pulmonary metastatic melanoma model of BALB/c mice. Expectedly, Bet-CA treatment significantly limited tumor growth and metastatic nodule formation in lungs. The results clearly authenticate the apparent synergistic antitumor behaviour of this compound in vivo. Histological appearances of the organs in treated sets were normal depicting no level of toxicity of Bet-CA.

From the above studies they presented an important consequential agenda that Bet-CA is endowed with ability to target and kill cancer cells. Their data clearly indicate that Bet-CA might be considered a capable drug as it enforces repression of cancer cell proliferation in vitro and tumor initiation and growth in vivo without any toxic manifestations. The conjunction of a plant secondary metabolite with a small molecule presents a promising synergistic and encouraging selective strategy to circumvent malignancy and obliterate cytotoxicity. Based on our findings further elucidation of detailed course of action of Bet-CA is a riveting area and likely to resonate a substantial promise for the future.

Reference

Suchandrima Saha, Monisankar Ghosh and Samir Kumar Dutta, A potent tumoricidal co-drug ‘Bet-CA’ – an ester derivative of betulinic acid and dichloroacetate selectively and synergistically kills cancer cells, Scientific Reports 5, Article number: 7762 ｜doi:10.1038/srep07762.