February 16, 2023
23/02/2023
February 16, 2023
LA JOLLA, CA Scientists at Scripps Research, with collaborators in Japan, have discovered how a poisoned form of a protein could set off a cascade of events that encourage the growth of some cancers. The research, published in Nature Communications on February 4, also triggered development of a drug candidate that can revert the protein to its normal form. In mice with colon cancer, the drug prevented or dramatically slowed formation of tumors.
This is a potentially very important and druggable link between the environment, genes and cancer, says senior author Stuart Lipton, MD, PhD, professor and Step Family Foundation Endowed Chair in the Department of Molecular Medicine at Scripps Research and a clinical neurologist in La Jolla, Calif.
The study was a collaboration with a team led by Takashi Uehara at Okayama University in Japan.
Lipton's research group previously discovered a process called protein S-nitrosylation, in which a molecule related to nitric oxide (NO) binds to sulfur atoms within proteins to change those proteins' functions. NO is found naturally within the body and produced in response to inflammation. But it also can form from nitrates and nitrites that are eaten (in the form of processed meats) or breathed in (through cigarette smoke or air pollution). Recently, the team showed how S-nitrosylation might contribute to Alzheimer's disease as well as Parkinson's disease, Lewy body dementia, Lou Gehrig's disease (ALS) and some forms of autism.
Separately, scientists know that many genes can be turned on or off by proteins called DNA methyltransferases (a process known as epigenetic control of gene expression). When these proteins add a methyl group a kind of chemical marker to a strand of DNA, they keep nearby genes from being activated. In some cancers, those methyl silencers are removed, and genes involved in tumor growth and spread get abnormally turned on.
If you block methylation, genes get turned on when they shouldn't be, and that's been known to be an important driver of some cancers, says Lipton. But no one knew the prime trigger for this process.
In the work, Lipton, with Scripps Research investigator Tomohiro Nakamura and their colleagues in Japan, showed that when DNA methyltrasferase 3B (DNMT3B) is S-nitrosylated which can happen in the presence of high levels of NO it no longer adds methyl groups to DNA. This then enables certain those cancer-causing genes to turn on. The findings suggest one way that processed meats, air pollution, cigarette smoke and inflammation all linked to some forms of cancer could flip DNMT3B to its cancer-promoting form.
It's like a poisoned form of DNMT3B, says Lipton.
The group went on to show that when DNMT3B is poisoned in this way, expression levels of 173 different genes in human cells changed. Among these genes is Ccnd2, which was already known to be involved in the formation of gastric and colon cancers in humans.
The research group in Japan then designed a drug that would prevent DNMT3B from being S-nitrosylated, but not block its normal function or affect the S-nitrosylation of any other proteins. This prevented NO, even when present at high levels, from converting DNMT3B into the poisoned form.
Lipton and Uehara's teams found that the drug, known as DBIC, prevented isolated precancerous colon cells from turning into full-blown colon cancer in the lab. Moreover, when they gave DBIC to mice prone to colon cancer, the drug virtually prevented tumors from forming, even when inflammation produced high levels of NO.
The researchers think that the S-nitrosylation of DNMT3B is likely associated with other cancers, including brain and breast cancer. They're planning more research on the full list of genes that are impacted by S-nitrosylated DNMT3B.
We still don't know the full panoply of tumor types that this molecular switch might be associated with, says Lipton. We'll be pursuing that in the future, as well as trying to move DBIC toward human clinical trials.
In addition to Lipton and Uehara, authors of the study, Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis, were Nhi Lang and Tomohiro Nakamura of Scripps Research; Kosaku Okuda, Kengo Nakahara, Yuta Iijima, Ryosuke Nomura, Kana Fujikawa, Kazuya Adachi, Yuki Shimada, Satoshi Fujio, Reina Yamamoto, Nobumasa Takasugi, Taichi Ukegawa, Yasuo Takeuchi, Norihisa Yasui and Atsuko Yamashita of Okayama University; Akihiro Ito of Tokyo University of Pharmacy and Life Sciences; Ashutosh Kumar and Kam Y. J. Zhang of RIKEN; Kunishige Onuma, Mitsuhiko Osaki and Futoshi Okada of Tottori University; Hiroyuki Marusawa of Kyoto University; Yosuke Matsushita and Toyomasa Katagiri of Tokushima University; Takahiro Shibata of Nagoya University; Koji Uchida of the University of Tokyo; and Sheng-Yong Niu of the Broad Institute of Harvard and MIT.
This work was supported by funding from the Ministry of Education, Culture, Sports and Technology of Japan (15H04649, 18H02579, 25670029, 15K14952, 17H06170), JSPS Research Fellowships (16J00339, 21J12602, 20J21060), JST (JPMJFS2128 ), JST SPRING (JPMJSP2126), the Translational Research Network Program (16lm0103011j0003), the Project for Cancer Research and Therapeutic Evolution (19cm0106436h0002) from the Japan Agency for Medical Research and Development, Joint Usage and Joint Research Programs, the Institute of Advanced Medical Sciences, Tokushima University, the National Institutes of Health (R01 AG061845, RF1 NS123298, R61 NS122098, DP1 DA041722, R01 AG056259, R01 AG078756, RF1 AG057409, R35 AG071734, TRDRP Grant 27IR-0010).
Can
LINK: | https://www.scripps.edu/news-and-events/press-room/2023/20230216-lipto... |
See more stories from scripps |
More from Scripps
20/04/2024
April 19, 2024
New copper-catalyzed C-H activation strategy from Scripps Research Two-mode reactions inspired by human detox enzymes offer powerful new tools for drug discover...
12/04/2024
April 11, 2024
Scripps Research chemists devise easier new method for making a common type of building block for drugs Scientists transform simple linear amines into saturated...
06/04/2024
April 05, 2024
A simple, inexpensive way to make carbon atoms bind together A Scripps Research team uncovers a cost-effective method for producing quaternary carbon molecules,...
04/04/2024
April 03, 2024
Developing a vaccine for the zombie drug xylazine Scripps Research chemical biologists design an early proof-of-concept vaccine that could lead to the first...
30/03/2024
March 29, 2024
How blocking a neural receptor responsible for addiction could reduce alcohol use A Scripps Research team found that a new therapeutic that targets the kappa op...
13/03/2024
March 13, 2024
New computational strategy boosts the ability of drug designers to target proteins inside the membrane Customized-design approach could streamline the design of...
29/02/2024
February 29, 2024
Scripps Research scientists reveal how first cells could have formed on Earth New phospholipid discovery brings researchers closer to understanding how primordi...
29/02/2024
February 28, 2024
How molecular handedness emerged in early biology Scripps Research chemists fill a major gap in origin-of-life theories. February 28, 2024 LA JOLLA, CA Mole...
22/02/2024
February 21, 2024
Snaking toward a universal antivenom Scripps Research scientists discovered antibodies that protect against a host of lethal snake venoms. February 21, 2024 ...
06/02/2024
February 06, 2024
Calibr-Skaggs announces expansion of option and license agreement with AbbVie to develop novel cell therapies for solid tumors and autoimmune diseases AbbVie...
26/01/2024
January 25, 2024
Re-energizing mitochondria to treat Alzheimer's disease Scripps Research team restored neuron-to-neuron connections in human cells. January 25, 2024 LA JO...
24/01/2024
January 04, 2024
100 years of Science Changing Life: Scripps Research celebrates a century of transforming human health For the last century, institute leaders and renowned scie...
23/01/2024
January 23, 2024
New technology lets researchers track brain cells' off switches The method could shed light on what goes awry in numerous brain conditions when neurons ar...
09/01/2024
January 08, 2024
Three decades of giving: Announcing the Calibr-Skaggs Institute for Innovative Medicines The ALSAM Foundation, founded by the Skaggs family, provides lasting g...
04/01/2024
January 03, 2024
Life science entrepreneur Gene Lay joins Scripps Research Board of Directors Lay, founder of the global biotech company BioLegend, brings invaluable experience ...
21/12/2023
December 20, 2023
Taming a plant-derived toxin Scripps Research team modifies the traditional poison picrotoxinin for potential neurological drugs and anti-parasite treatments. ...
19/12/2023
December 18, 2023
Scripps Research Executive Vice President Eric Topol gives TED talk on transformative power of AI in medicine Topol provides an overview of how AI models can i...
13/12/2023
December 12, 2023
New AI-powered algorithm could better assess people's risk of common heart condition Early detection of atrial fibrillation can reduce the risk of stroke an...
07/12/2023
December 06, 2023
Nanoparticle flu vaccine design shows promise in early tests Scripps Research-designed vaccine could provide broad, enduring protection against influenza A str...
16/11/2023
November 15, 2023
Numerous Scripps Research scientists named Highly Cited Researchers Clarivate's annual, global list represents researchers who have demonstrated significant...
07/11/2023
November 06, 2023
Multiple sclerosis drug invented at Scripps Research slows long-term devastating disease progression Late-breaking data reinforces the effectiveness and safety ...
05/10/2023
October 04, 2023
Keren Lasker named a 2023 Moore Inventor Fellow The prestigious award will support Lasker's inventive research in membraneless organelles and their applica...
22/09/2023
September 21, 2023
Michael Bollong named a 2023 Amgen Young Investigator The prestigious award will support Bollong's research identifying new molecular targets and therapeuti...
09/09/2023
September 08, 2023
Philip Dawson receives 2024 American Chemical Society National Award Dawson is honored with the Arthur C. Cope Late Careers Scholar Award for his foundational c...
07/09/2023
September 06, 2023
Scripps Research chemists devise a method for C-H activation of alcohols The method represents a new toolkit for making drugs and other compounds. September 06...
31/08/2023
August 30, 2023
Scripps Research receives $1.5M to surveil infectious disease threats in wastewater Bill & Melinda Gates Foundation award to support the development of multi-pa...
16/08/2023
August 16, 2023
How cold temperatures trigger the brain to boost appetite Scripps Research scientists' discovery could lead to new weight loss and metabolic health treatmen...
08/08/2023
August 07, 2023
Human antibody that targets carfentanil, fentanyl and related opioids reverses overdose effects in preclinical study Scripps Research-developed antibody therapy...
04/08/2023
August 03, 2023
How sensory neurons impact the gut Scripps Research scientists show that the receptor PIEZO2 in sensory neurons controls gut motility and transit time, which a...
26/07/2023
July 26, 2023
AbbVie and Calibr Expand Strategic Collaboration to Advance Several Preclinical and Early-stage Clinical Assets The expanded strategic collaboration will advan...
23/07/2023
July 21, 2023
Scripps Research scientists develop AI-based tracking and early-warning system for viral pandemics Machine-learning system effectively predicts emergence of pro...
19/07/2023
July 19, 2023
Monitoring T cells may allow prevention of type 1 diabetes Scripps Research study shows that analyzing T cells in blood samples could be used to select at-risk ...
19/07/2023
July 18, 2023
Scripps Research mourns passing of leading organic chemist Albert Eschenmoser Eschenmoser pioneered key reactions in synthetic chemistry and shaped the understa...
15/06/2023
June 14, 2023
Scripps Research awarded $46.8 million by NIH to promote human health through innovative translational science and training The Translational Institute is harne...
13/06/2023
June 13, 2023
Scripps Research's Danielle Grotjahn named 2023 Pew Scholar in the Biomedical Sciences The award will support Grotjahn's study of how cells assemble the...
31/05/2023
May 31, 2023
Crossing the ring: new method enables C-H activation across saturated carbocycles Scripps Research chemists add another powerful tool to their molecular editin...
24/05/2023
May 23, 2023
Scripps Research develops behind-the-scenes tool for better biomedical data discovery The new resource makes datasets more discoverable for life science communi...
19/05/2023
May 15, 2023
Scripps Research neuroscientist Hollis Cline elected to American Academy of Arts and Sciences Cline is recognized for her discoveries about the role of sensory ...
19/05/2023
May 18, 2023
Scripps Research's Skaggs Graduate School awards doctoral degrees to 31st graduating class Commencement ceremony will be livestreamed via Zoom and on instit...
13/05/2023
May 12, 2023
A better route to benzocyclobutenes, sought-after building blocks for drugs Scripps Research chemists devise a new, C-H activation-based method for the synthesi...
09/05/2023
May 08, 2023
Renowned Scripps Research professor Jeffery Kelly elected to National Academy of Sciences Kelly's groundbreaking work on protein misfolding has led to thera...
28/04/2023
April 27, 2023
Mirror-image molecules pave new path for cancer drug discovery By comparing how mirror image versions of small molecules impact clusters of proteins, Scripps R...
22/04/2023
April 21, 2023
How alcohol consumption contributes to chronic pain A Scripps Research team showed how both alcohol intake and alcohol withdrawal can lead to increased pain and...
21/04/2023
April 20, 2023
Xin Jin receives dual awards to study autism risk genes in neurodevelopment Major grants from the National Institutes of Health and California Institute for Reg...
20/04/2023
April 19, 2023
Trim the sugar: New HIV vaccine design improves immune response Scripps Research vaccine candidate headed for clinical trials. April 19, 2023 LA JOLLA, CA A...
18/04/2023
April 17, 2023
Therapeutic can seek and destroy potent opioid to treat overdoses Scripps Research chemists developed a new biologic to work against the synthetic opioid carfen...
07/03/2023
March 06, 2023
How heavy alcohol consumption increases brain inflammation The findings by a Scripps Research team point toward a potential new drug target for treating alcohol...
02/03/2023
March 01, 2023
Scientists find human antibodies that can block multiple coronaviruses including SARS-CoV-2 Results from a Scripps Research and UNC team pave the way for a vacc...
28/02/2023
February 28, 2023
$10 million grant funds Scripps Research Alcohol Research Center through its 50th year The five-year grant supports research into the neurobiology of alcohol us...
28/02/2023
February 27, 2023
Immune system drug shows promise in treating alcohol use disorder, a Scripps Research clinical trial reports Scientists at Scripps Research found that apremilas...