Piperlongumine, chemical from Indian pepper plant inhibits enzyme in cancer cells

UT Southwestern Medical Center scientists have uncovered the chemical process behind anti-cancer properties of a spicy Indian pepper plant called the long pepper, whose suspected medicinal properties date back thousands of years. The study is published in the Journal of Biological Chemistry.

Dr. Westover’s lab used X-ray crystallography to create this molecular model of piperlongumine.
Credit: UT Southwestern

The secret lies in a chemical called Piperlongumine (PL), which has shown activity against many cancers including prostate, breast, lung, colon, lymphoma, leukemia, primary brain tumors, and gastric cancer.

Using x-ray crystallography, researchers were able to create molecular structures that show how the chemical is transformed after being ingested. Piperlongumine (PL) converts to hPiperlongumine (hPL), an active drug that silences a gene called GSTP1. The GSTP1 gene produces a detoxification enzyme Glutathione S-Transferase Pi 1 that is often overly abundant in tumors.

“We are hopeful that our structure will enable additional drug development efforts to improve the potency of PL for use in a wide range of cancer therapies,” said Dr. Kenneth Westover, Assistant Professor of Biochemistry and Radiation Oncology. “This research is a spectacular demonstration of the power of x-ray crystallography.”

Dr. Westover, a member of the Harold C. Simmons Comprehensive Cancer Center, used cutting edge technologies in UT Southwestern’s Structural Biology Core (SBC) – the University’s world-renowned facility for X-ray crystallography, to better understand the anticancer properties of Piperlongumine (PL). X-ray crystallography allows scientists to determine molecular structures that reveal how molecules interact with targets – in this case how Piperlongumine (PL) interacts with GSTP1. Viewing the structures helps in developing drugs for those targets.

Citation: Harshbarger, Wayne, Sudershan Gondi, Scott B. Ficarro, John Hunter, Durga Udayakumar, Deepak Gurbani, William Singer, Yan Liu, Lianbo Li, Jarrod A. Marto and Kenneth D. Westover. “Structural and Biochemical Analyses Reveal the Mechanism of Glutathione S-Transferase Pi 1 Inhibition by the Anti-cancer Compound Piperlongumine.” Journal of Biological Chemistry (2016): jbc-M116.
DOI: 10.1074/jbc.M116.750299
Research funding: V Foundation for Cancer Research, Welch Foundation, and Cancer Prevention and Research Institute of Texas.
Adapted from press release by UT Southwestern Medical Center.

Calcium channel blockers used for hypertension has potential to block cancer invasion

By screening already approved drugs, the team led by Postdoctoral Researcher Guillaume Jacquemet and Academy Professor Johanna Ivaska has discovered that calcium channel blockers can efficiently stop cancer cell invasion in vitro. Calcium channel blockers are currently used to treat hypertension, also known as high blood pressure, but their potential use in blocking cancer cell metastases has not been previously reported.

High-resolution microscope image of an invasive breast cancer cell (magenta) expressing
Myosin-10 induced “sticky-fingers” (green). Credit: Dr Guillaume Jacquemet, University of Turku.

Cancer kills because of its ability to spread throughout the body and form metastases. Therefore, developing drugs that block the ability of cancer cells to disseminate is a major anti-cancer therapeutic avenue. Developing new drugs, however, is a very lengthy and expensive process and many promising drugs fail clinical trials because of unanticipated toxicity and side effects. Thus, finding new targets for drugs already in use to treat other diseases, in other words, drug repurposing, is an emerging area in developing anti-cancer therapies.

Identification of anti-hypertension drugs as potential therapeutics against breast and pancreatic cancer metastasis was a big surprise. The targets of these drugs were not known to be present in cancer cells and therefore no one had considered the possibility that these drugs might be effective against aggressive cancer types, says Professor Ivaska.

For several years, the research team from the Turku Centre for Biotechnology lead by Professor Johanna Ivaska has focused their efforts on understanding how cancer cells move and invade surrounding tissue. The team has identified that aggressively spreading cancer cells express a protein called Myosin-10 which drives cancer cell motility.

Myosin-10 expressing cancers have a large number of structures called filopodia. They are sticky finger-like structures the cancer cells extend to sense their environment and to navigate – imagine a walking blind spider, explains Dr. Jacquemet.

The team found that calcium channel blockers target specifically these sticky fingers rendering them inactive, thus efficiently blocking cancer cell movement. This suggests that they might be effective drugs against cancer metastasis. However, at this stage, much more work is required to assess if these drugs would be efficient against cancer progression.

The team and their collaborators are currently assessing the efficiency of calcium channel blockers to stop the spreading of breast and pancreatic cancer using pre-clinical models and analyzing patient data. The findings were published in Nature Communications journal.

Citation: Jacquemet, Guillaume, Habib Baghirov, Maria Georgiadou, Harri Sihto, Emilia Peuhu, Pierre Cettour-Janet, Tao He, Merja Perälä, Pauliina Kronqvist, Heikki Joensuu & Johanna Ivaska. “L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling.” Nature Communications 7 (2016): 13297.
DOI:10.1038/ncomms13297
Adapted from press release by the University of Turku.

New approach to targeted cancer treatment and imaging by utilizing glycosidase activation of glyconaphthalimides.

Scientists from Trinity College Dublin have uncovered a new class of compounds glyconaphthalimides that can be used to target cancer cells with greater specificity than current options allow. The study was published in the journal Chemical Communications.

Cervical cancer cells show green fluorescence from enzyme-activated compound.
Credit: Eoin Scanlan, Trinity College Dublin.

Cancer is difficult to treat, and many current therapies are unable to specifically target cancer cells. This is problematic for medical professionals and patients, because it limits the dose of the drug that can be safely administered, and often causes severe and debilitating side-effects.

But the Trinity scientists have now demonstrated that a class of naturally occurring enzymes  glycosidases  that are heavily overexpressed in tumor tissue can be used to trigger the release of therapeutic payloads only in the local tumor sites where they are needed.

This finding may therefore result in the development of improved targeted cancer therapies with significantly reduced side-effects for patients.

In addition to killing cancer cells, the technology may also be used to image cancer cells, with potential applications in cancer imaging and diagnosis.

Associate Professor in Chemistry at Trinity, Eoin Scanlan, led the multidisciplinary group. He said: “This is a really exciting discovery because it brings us closer to more targeted treatment of cancer. Some current therapies are limited due to the toxicity of the compounds, but our compounds are completely inactive until they are released by the enzymes that are naturally overexpressed at the tumour site. The active compound is then rapidly taken up by cancer cells.”

“Our next steps will be to apply this technology to release specific anti-cancer drugs and to test it against a range of different cancer types.”

Citation: Calatrava-Pérez, Elena, Sandra A. Bright, Stefan Achermann, Claire Moylan, Mathias O. Senge, Emma B. Veale, D. Clive Williams, Thorfinnur Gunnlaugsson, and Eoin M. Scanlan. “Glycosidase activated release of fluorescent 1, 8-naphthalimide probes for tumor cell imaging from glycosylated ‘pro-probes’.” Chemical Communications 52, no. 89 (2016): 13086-13089.
DOI: 10.1039/C6CC06451E 
Research funding: Science Foundation Ireland.
Adapted from press release by Trinity College Dublin.

Research shows possible link between "body clock" and cancer pathogenesis

A new study led by scientists at The Scripps Research Institute (TSRI) describes an unexpected role for proteins involved with our daily “circadian” clocks in influencing cancer growth. The research, published in the journal Molecular Cell, suggests that disruptions in circadian rhythms might leave levels of an important cancer-linked protein, called cMYC, unchecked.

“This appears to have big implications for the connection between circadian rhythms and cancer,” said TSRI biologist Katja Lamia, senior author of the study.

There is growing evidence that shift work and frequent jet lag can raise a person’s risk of cancer, suggesting a link between daily rhythms and cell growth. “We know this connection exists, but we haven’t known why,” said Lamia.

The researchers focused on proteins called cryptochromes, which evolved from bacterial proteins that sense light and repair DNA damage caused by sunlight. In humans, these proteins, called CRY1 and CRY2, regulate our circadian clocks, which influence what times of day we become tired, hungry and much more.

Using cells from mouse models, the researchers demonstrated that deleting the gene that expresses CRY2 reduced the cells’ ability to degrade a protein called cMYC. Without CRY2 keeping cMYC at normal levels, the researchers saw increased cell proliferation similar to the abnormal growth seen in cancers.

Further studies of protein structures suggested that CRY2 is a key player in a process to “mark” cMYC for degradation. The researchers said it is significant that this process occurs after gene transcription once the proteins are already produced rather than during transcription, as in many other cryptochrome functions.

“This is a function of a circadian protein that has never been seen before,” said TSRI Research Associate Anne-Laure Huber, who served as first author of the study.

The researchers say more studies are needed to confirm this connection between circadian clocks and cancer in human tissues.

Citation: “CRY2 and FBXL3 Cooperatively Degrade c-MYC”. Anne-Laure Huber, Stephanie J. Papp, Alanna B. Chan, Emma Henriksson, Sabine D. Jordan, Anna Kriebs, Madelena Nguyen, Martina Wallace, Zhizhong Li, Christian M. Metallo, Katja A. Lamia. Molecular Cell 2016 vol: 64 (4) pp: 774-789.
DOI: 10.1016/j.molcel.2016.10.012
Research funding: National Institutes of Health, Searle Scholars Program through the Kinship Foundation, Sidney Kimmel Foundation, Lung Cancer Research Foundation, Swedish Research Council, Deutsche Forschungsgemeinschaft and American Heart Association.
Adapted from press release by The Scripps Research Institute.

Research shows possible link between “body clock” and cancer pathogenesis

A new study led by scientists at The Scripps Research Institute (TSRI) describes an unexpected role for proteins involved with our daily “circadian” clocks in influencing cancer growth. The research, published in the journal Molecular Cell, suggests that disruptions in circadian rhythms might leave levels of an important cancer-linked protein, called cMYC, unchecked.

“This appears to have big implications for the connection between circadian rhythms and cancer,” said TSRI biologist Katja Lamia, senior author of the study.

There is growing evidence that shift work and frequent jet lag can raise a person’s risk of cancer, suggesting a link between daily rhythms and cell growth. “We know this connection exists, but we haven’t known why,” said Lamia.

The researchers focused on proteins called cryptochromes, which evolved from bacterial proteins that sense light and repair DNA damage caused by sunlight. In humans, these proteins, called CRY1 and CRY2, regulate our circadian clocks, which influence what times of day we become tired, hungry and much more.

Using cells from mouse models, the researchers demonstrated that deleting the gene that expresses CRY2 reduced the cells’ ability to degrade a protein called cMYC. Without CRY2 keeping cMYC at normal levels, the researchers saw increased cell proliferation similar to the abnormal growth seen in cancers.

Further studies of protein structures suggested that CRY2 is a key player in a process to “mark” cMYC for degradation. The researchers said it is significant that this process occurs after gene transcription once the proteins are already produced rather than during transcription, as in many other cryptochrome functions.

“This is a function of a circadian protein that has never been seen before,” said TSRI Research Associate Anne-Laure Huber, who served as first author of the study.

The researchers say more studies are needed to confirm this connection between circadian clocks and cancer in human tissues.

Citation: “CRY2 and FBXL3 Cooperatively Degrade c-MYC”. Anne-Laure Huber, Stephanie J. Papp, Alanna B. Chan, Emma Henriksson, Sabine D. Jordan, Anna Kriebs, Madelena Nguyen, Martina Wallace, Zhizhong Li, Christian M. Metallo, Katja A. Lamia. Molecular Cell 2016 vol: 64 (4) pp: 774-789.
DOI: 10.1016/j.molcel.2016.10.012
Research funding: National Institutes of Health, Searle Scholars Program through the Kinship Foundation, Sidney Kimmel Foundation, Lung Cancer Research Foundation, Swedish Research Council, Deutsche Forschungsgemeinschaft and American Heart Association.
Adapted from press release by The Scripps Research Institute.

Liquid biopsies for lung cancer could predict best treatment

A blood test could predict how well small-cell lung cancer (SCLC) patients will respond to treatment, according to new research published in Nature Medicine today. Scientists, based at the Cancer Research UK Manchester Institute at The University of Manchester, isolated tumor cells that had broken away from main cancer known as circulating tumor cells (CTCs) – from the blood of 31 patients with this aggressive form of the disease. When researchers analyzed these cells, they discovered that patterns of genetic faults measured before treatment were linked to how well and how long a patient might respond to chemotherapy.

Obtaining a tumor sample from lung cancer patients using an operation, known as a biopsy, can be difficult because the tumor is hard to reach and samples are often too small to reveal useful clues on how best to treat patients. Liquid biopsies offer an alternative to taking tumor samples, providing a snapshot of the disease from a blood sample.

The team also investigated the genetic changes that occurred in patients who initially responded well to treatment but later relapsed. The pattern in these cells was different from patients who didn’t respond well to chemotherapy, suggesting different mechanisms of drug resistance had developed.

Lead researcher Professor Caroline Dive, based at the Cancer Research UK Manchester Institute, said: “Our study reveals how blood samples could be used to anticipate how lung cancer patients may respond to treatments”. Unfortunately, we have very few treatment options for patients with SCLC and none at all for those whose cancer is resistant to chemotherapy. “By identifying differences in the patterns of genetic faults between patients, we now have a starting point to begin to understand more about how drug resistance develops in patients with this aggressive form of lung cancer.”

Dr. Emma Smith, Cancer Research UK’s science information manager, said: “Lung cancer causes more than one in five of all cancer deaths in the UK and it’s vital that we find effective new treatments to fight the disease and save more lives. “These liquid biopsies are an incredibly exciting area of research. Studies like this help build a bigger picture of the disease, pointing the way to developing new treatments that are urgently needed for people with lung cancer.”

Citation: “Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer”. Louise Carter, Dominic G Rothwell, Barbara Mesquita, Christopher Smowton, Hui Sun Leong, Fabiola Fernandez-Gutierrez, Yaoyong Li, Deborah J Burt, Jenny Antonello, Christopher J Morrow, Cassandra L Hodgkinson, Karen Morris, Lynsey Priest, Mathew Carter, Crispin Miller, Andrew Hughes, Fiona Blackhall, Caroline Dive & Ged Brady. Nature Medicine 2016.
DOI: http://dx.doi.org/10.1038/nm.4239
Adapted from press release by the University of Manchester.

Obese patients with monoclonal gammopathy of undetermined significance (MGUS) are at higher risk of progression to multiple myeloma

New research shows that excess weight increases the risk that a benign blood disorder will progress into multiple myeloma, a cancer of the blood. The study, by a team at Washington University School of Medicine in St. Louis, is published Nov. 18 in the Journal of the National Cancer Institute.

Being overweight or obese has been known to increase the risk of multiple myeloma, a cancer of the plasma cells in the blood and bone marrow that develops more often after age 60. Multiple myeloma is preceded by a blood disorder called monoclonal gammopathy of undetermined significance (MGUS) in which abnormal plasma cells produce many copies of an antibody protein. This precancerous condition does not cause symptoms and often goes undiagnosed.

“But our findings show that obesity can now be defined as a risk factor for developing multiple myeloma through this condition,” said the study’s first author, Su-Hsin Chang, Ph.D., an assistant professor of surgery in the Division of Public Health Sciences at Washington University. “For patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS), maintaining a healthy weight may be a way to prevent the progression to multiple myeloma, if further confirmed by clinical trials.”

The researchers analyzed data from a U.S. Department of Veterans Affairs database, identifying 7,878 patients, predominately men, diagnosed with monoclonal gammopathy of undetermined significance (MGUS) from October 1999 through December 2009.

Among these patients, 39.8 percent were overweight and 33.8 percent were obese. The researchers then tracked whether the patients developed multiple myeloma. They found that 4.6 percent of overweight patients (followed for a median of 5.75 years) and 4.3 percent of obese patients (followed for a median of 5.9 years) developed multiple myeloma, compared with 3.5 percent of people at normal weight (followed for a median of 5.2 years) – a difference that is statistically significant.

Overweight and obese monoclonal gammopathy of undetermined significance (MGUS) patients had a 55 percent and 98 percent higher risk of progression to multiple myeloma, respectively, than normal-weight MGUS patients.

African-American men also were more likely than their Caucasian counterparts to experience a progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma.

Monoclonal gammopathy of undetermined significance (MGUS) is caused by elevated levels of an antibody protein, known as M protein, that is found in 3 percent of people over age 50. By itself, MGUS is difficult to diagnose and often does not warrant treatment. “The diagnosis is usually by accident, often driven by tests performed for the diagnosis or management of other conditions,” Chang said. “Although our study does not directly suggest screening for MGUS, regular check-ups can help physicians monitor whether MGUS is progressing to other disorders, including multiple myeloma.”

Multiple myeloma is the third most common type of blood cancer. An estimated 30,330 new cases of multiple myeloma will be diagnosed in 2016, and 12,650 deaths will be attributed to the disease, according to the American Cancer Society.

“Based on our finding that being overweight or obese is a risk factor for multiple myeloma in MGUS patients, and since extra weight is a modifiable risk factor, we hope that our results will encourage intervention strategies to prevent the progression of this condition to multiple myeloma as soon as MGUS is diagnosed,” Chang said. “Also, for black people diagnosed with MGUS, close monitoring of the disease progression, in addition to maintaining a healthy weight, should be prioritized.”

Future studies are planned by Chang and other School of Medicine researchers – including senior author Kenneth R. Carson, MD, PhD, an assistant professor of oncology, and Graham Colditz, MD, DrPH, a cancer expert who also is associate director of prevention and control at Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital. “In the future, we will look at whether healthy weight loss is inversely associated with the progression of multiple myeloma in MGUS patients or how weight change plays a role in the progression of MGUS to multiple myeloma,” Chang said.

Citation: Chang SH, Luo S, Thomas TS, O’Brian KK, Colditz GA, Carlsson NP, Carson KR. Obesity and the Transformation of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma: A Population-Based Cohort Study. Journal of the National Cancer Institute. Nov. 18, 2016.
DOI:
Research funding: Foundation for Barnes-Jewish Hospital, Siteman Cancer Center, National Institutes of Health, Agency for Healthcare Research and Quality, American Cancer Society.
Adapted from press release by Washington University School of Medicine in St. Louis.

Protein CPEB4 plays crucial role in melanoma

Spanish National Cancer Research Centre (CNIO) Melanoma Group researchers work tirelessly to identify biomarkers of tumor progression and to validate novel therapeutic targets in melanoma. In particular, their research focuses on discovering features that define the “fingerprint” of this tumor, features that distinguish it from other cancer types. The latest study in this area, published in Nature Communications, describes the roles of CPEB4; a protein that is crucial for melanoma cell survival. The group headed by Marisol Soengas, senior author of this paper, is an expert in researching the “identity” of melanomas.

High levels of CPEB4 expression in human melanoma. The image shows a melanoma
biopsy stained for CPEB4 factor (in red) and one of its target genes (RAB27, in green).
Credit: Centro Nacional de Investigaciones Oncológicas (CNIO)

“In previous studies, we have demonstrated that melanomas are very different from other types of tumors in that they activate mechanisms of self-degradation (autophagy), or control the internalization and secretion of molecules, for example,” explains Soengas. They have now found that the CPEB4 protein, which is of great interest in the cancer field, plays a selective and essential role in melanoma cells.

In broad terms, CPEBs are involved in the regulation of gene expression and are associated with important cellular processes, such as cell division, cell differentiation, or cell polarity and migration. In tumors, the expression of CPEBs varies, and seemingly opposing, pro- and antitumor, roles have been described in other tumor types but not in melanoma.

CPEB4, a member of this family, was “especially attractive” to the authors “given its overexpression in tumors such as gliomas and pancreatic carcinomas, which are also aggressive”. As they noted, the levels of this protein were very high in melanoma from the early stages of the disease, which made the researchers suspect its association with cell proliferation. What they did not know was the extent of it.

Soengas’ group compared the effects of CEPB4 on various tumors, and noted that melanoma cells were “more dependent on this protein”, since its inhibition greatly hindered the proliferation of these cells. This ‘addiction’ makes melanoma more vulnerable to drugs targeting this pathway, and can be a novel target for therapeutic intervention in melanoma.

The researchers also describe that melanomas depend so tightly on CPEB4 because this protein regulates the expression of factors such as MITF and RAB27A, which have unique functions in this tumor type. CPEB4, is therefore a main driver of the “intrinsic signature” that separates melanomas from other pathologies, concludes Soengas.

Citation: “Lineage-specific roles of the cytoplasmic polyadenylation factor CPEB4 in the regulation of melanoma drivers”. Eva Pérez-Guijarro, Panagiotis Karras, Metehan Cifdaloz, Raúl Martínez-Herranz, Estela Cañón, Osvaldo Graña, Celia Horcajada-Reales, Direna Alonso-Curbelo, Tonantzin G. Calvo, Gonzalo Gómez-López, Nicolas Bellora, Erica Riveiro-Falkenbach, Pablo L. Ortiz-Romero, José L. Rodríguez-Peralto, Lorena Maestre, Giovanna Roncador, Juan C. de Agustín Asensio, Colin R. Goding, Eduardo Eyras, Diego Megías, Raúl Méndez & María S. Soengas.
Nature Communications, 2016 vol: 7 pp: 13418.
DOI: http://dx.doi.org/10.1038/ncomms13418
Research funding: Marató TVE, Spanish Ministry of Economy and Competitiveness, Fundación Botín, Banco Santander, Spanish Ministry of Health, Fundación Sandra Ibarra, Ludwig Institute for Cancer Research
Adapted from press release by Centro Nacional de Investigaciones Oncológicas (CNIO)

Arecoline, stimulant from areca nut found to have anticancer properties

Researchers at Winship Cancer Institute of Emory University have discovered  that Arecoline, the stimulant component of areca nuts has anticancer properties. The findings are scheduled for publication in Molecular Cell.

This is a ripe areca nut and the the chemical structure of arecoline

Areca nuts are chewed for their stimulant effects in many Asian countries, and evidence links the practice to the development of oral and esophageal cancer. Analogous to nicotine, arecoline was identified as an inhibitor of the enzyme ACAT1, which contributes to the metabolism-distorting Warburg effect in cancer cells.

Jing Chen, PhD, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute says that arecoline could be compared to arsenic, a form of which is used as a treatment for acute promyelocytic leukemia, but is also linked to several types of cancer. Plus, arecoline’s cancer-promoting effects may be limited if it is not delivered or absorbed orally, he says.

The Warburg effect, named after 1931 Nobel laureate Otto Warburg, describes how cancer cells tend to favor the inefficient use of glucose, known as glycolysis, and de-emphasize their mitochondria. Cancer cells benefit from this metabolic distortion because the byproducts of glycolysis can be used as building blocks for fast growth.

Chen’s laboratory had previously identified the mitochondrial thiolase ACAT1 (acetyl-CoA acetyltransferase) as a control valve regulating the Warburg effect. In this paper, the researchers showed that ACAT1 enzymatic activity was higher in several types of cancer cells, even though the levels of ACAT1 protein are about the same. The reason is that the protein clusters together as tetramers in cancer cells. Tyrosine kinases, often on overdrive in cancer cells, “hijack” ACAT1 and nudge it into tetramers, which are enzymatically more active.

But arecoline, identified in a screen of 2000 FDA-approved small molecule compounds, can inhibit ACAT1 and prevent it from forming tetramers. Arecoline forms a chemical bond with part of the ACAT1 protein, the researchers showed.

Arecoline appears to do what the researchers proposed it would: it steers cells’ metabolism away from glycolysis. The compound inhibited the growth of human lung cancer and leukemia cells both in culture and grafted into mice, and did not affect the growth of normal blood cells.

The enzyme ACAT1 seems to have a double role. It breaks down ketones and the amino acid isoleucine, and it also modifies other proteins through acetylation, which is how it regulates the Warburg effect.

Genetic mutations in ACAT1 lie behind a very rare metabolic disorder called beta-ketothiolase deficiency. Complete inhibition of ACAT1 could induce side effects resembling that disorder. But when the Winship team incompletely “knocked down” ACAT1 in cells using arecoline or genetic tools, the main effect was on protein acetylation, not on ketone metabolism, Chen says.

While the researchers did not see obvious toxicity when treating mice with arecoline, more extensive pharmacokinetic and toxicology studies with arecoline and similar compounds are needed, he says.

Citation: “Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth”
Jun Fan, Ruiting Lin, Siyuan Xia, Dong Chen, Shannon E. Elf, Shuangping Liu, Yaozhu Pan, Haidong Xu, Zhiyu Qian, Mei Wang, Changliang Shan, Lu Zhou, Qun-Ying Lei, Yuancheng Li, Hui Mao, Benjamin H. Lee, Jessica Sudderth, Ralph J. DeBerardinis, Guojing Zhang, Taofeek Owonikoko, Manila Gaddh, Martha L. Arellano, Hanna J. Khoury, Fadlo R. Khuri, Sumin Kang, Paul W. Doetsch, Sagar Lonial, Titus J. Boggon, Walter J. Curran1, Jing Chen.
Molecular Cell 2016
DOI: http://dx.doi.org/10.1016/j.molcel.2016.10.014
Research funding: National Cancer Institute, T.J. Martell Foundation,  American Cancer Society seed grant and Georgia Cancer Coalition.
Adapted from press release by Emory Health Sciences.

Over expression of protein BRD4 associated with breast cancer metastasis

Researchers have identified a new pathway and with it a protein, BRD4, necessary for breast cancer cells to spread. The findings, which appear in the journal Cancer Research, may provide a new target to suppress breast cancer metastasis.

Triple-negative breast cancer is considered the worst subgroup of breast cancer. It is highly aggressive and responds poorly to the current therapeutic tools resulting in a dismal prognosis for patients. Furthermore, the lack of identified targets has limited the development of new drug strategies.

Researchers from Boston University School of Medicine (BUSM) used breast cancer cell lines that present the clinical characteristics of an aggressive breast cancer subtype (clinically described as a triple-negative breast cancer). They then used an experimental design to model cancer cell metastasis. By suppressing the expression of the protein BRD4 in these cell lines, they observed that their dissemination capabilities were blocked, indicating that BRD4 drives breast cancer dissemination. In addition, they conducted a screening analysis of human breast tumors and found that tumors with a high expression of BRD4 were more likely to metastasize.

“The current treatment options for a triple-negative cancer are unacceptably limited. It is crucial to identify new therapeutic targets to tackle challenging cancer types, including triple negative breast cancer. BDR4 targeting represents an innovative strategy to ablate breast cancer metastasis,” explained lead investigator Guillaume Andrieu, PhD, a post-doctoral research associate at Boston University School of Medicine.

Although obesity per se is not thought of as a carcinogen, the abnormal, inflamed microenvironments found in obesity are critical for progression, invasion and metastasis of triple negative breast cancer. “Bromodomain and ExtraTerminal domain (BET) proteins, which include BRD2, BRD3 and BRD4, are known to regulate production of inflammatory mediators. Our study proposes that BRD4 couples inflammation to breast cancer dissemination. Thus, small molecules that block BET proteins possess anti-inflammatory properties that can be useful for therapy,” he added.

Although these findings primarily focus on breast cancer and metastasis, the researchers plan to expand their results to the treatment of prostate cancer, which they believe has similar pathways involved in its metastasis.

Citation: Andrieu, Guillaume, Anna H. Tran, Katherine J. Strissel, and Gerald V. Denis. “BRD4 regulates breast cancer dissemination through Jagged1/Notch1 signaling.” Cancer Research (2016): canres-0559.
DOI: http://dx.doi.org/10.1158/0008-5472.CAN-16-0559
Research funding: NIH/National Cancer Institute
Adapted from press release by Boston Univsersity School of Medicine