Dieter Wolf Archives - Sanford Burnham Prebys

Tag: Dieter Wolf

Institute News

New study honors SBP scientist Marcia Dawson

AuthorSusan Gammon
Date

June 11, 2018

Marcia Dawson post

Professor Marcia Dawson was a fixture at Sanford Burnham Prebys for more than 25 years. The Stanford-educated biochemist was particularly interested in synthesizing compounds that induce apoptosis (programmed cell death) in tumors. Dawson passed away in 2016, but her work has continued.

Recently, researchers investigated several variations of a compound produced in the Dawson laboratory, called DIM-Ph-4-CF3. This molecule is designed to modulate a nuclear receptor protein called NR4A1. In this paper, published in the journal Oncotarget, the multi-lab team investigated whether oxidized versions of the compound could be even more potent against cancer.

“We tested a number of analogs, and I think the most interesting thing is that the oxidation products were more potent than their parent form,” said Marisa Sanchez, a PhD candidate in the lab of Dieter Wolf, PhD, and the first author on the paper. “This potency was exhibited by a significant decrease of cell viability in multiple cancer lines. They kill cancer very well.”

The NR4A1 receptor is usually found in the cell’s nucleus and cytoplasm. When modulated by the DIM-Ph-4-CF3 products, the cytoplasmic fraction appears to trigger the unfolded protein response, a cellular stress mechanism that often leads to apoptosis. The anti-cancer molecules showed particularly strong activity in prostate cancer and exhibited no obvious side effects.

As work continues on these molecules, they could potentially be used to augment the cancer-killing impact of chemotherapy or other treatments. Over time, cancer cells can evolve the ability to resist apoptosis, and this approach might work synergistically with existing therapies to overcome that resistance.

“They target those pathways in a different way to induce cell death,” says Sanchez. “It might be harder for cancers to develop resistance.”

Still, it’s quite early in the discovery process, and much more work needs to be done. Sanchez feels that further investigation could confirm the mechanism of action and perhaps make the molecule more specific.

In addition to being a rewarding effort to develop and test new anticancer molecules, this was a labor of love for the research team, several of whom had worked with Dawson for decades.

“We finished this in Marcia’s memory,” says Sanchez. “We really wanted to honor her.”

Institute News

How the enzymes that “tidy up” a cell are turned off and on

AuthorJessica Moore
Date

January 17, 2017

generic cell-related

When a cell has too much of a certain kind of machine or sensor, the extras are tagged for destruction. That tagging is carried out by enzymes that serve as the cell’s professional organizers, going through everything and deciding what’s not needed. These enzymes, called ubiquitin ligases because the tag they attach is named ubiquitin, are really important. If they don’t work right, cell parts that should be broken down instead hang around, or useful components are unnecessarily destroyed, which can cause major problems.

When ubiquitin ligases in a class called Nedd4 don’t work properly, they can contribute to diseases including Parkinson’s, epilepsy, inherited blood pressure disorders, and certain cancers. That’s because Nedd4 ligases regulate the amounts of cell components that control electrical activity in neurons, responses to brain chemicals and cell growth. To better understand Nedd4 ligases, a team of scientists including Dieter Wolf, MD, professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), looked at how they’re turned off and on.

“We found that when Nedd4 ligases are turned off, they cluster together in groups of three,” says Wolf. “That happens because ubiquitin attaches to a certain part of the enzyme, moving it in a way that exposes another part that likes to stick to other Nedd4 ligases.”

Wolf and Khatereh Motamedchaboki, PhD, director of SBP’s proteomics core, did the proteomics analysis for the paper, published in the EMBO Journal. Those data were crucial for showing that ubiquitin is attached to the inactive form of Nedd4. The study was led by Gali Prag, PhD, a professor at Tel Aviv University.

“These results show that Nedd4 activity can be modulated—and that could open up a new approach to treating certain neurological disorders,” Wolf adds. “Once we understand more about these enzymes—for example, whether most Nedd4 ligases in a normal cell are in the active or the inactive form, and what the trigger is for ubiquitin to attach to Nedd4—we may be able to develop a new strategy for treating diseases linked to this enzyme, like Parkinson’s.”

The paper is available online here.

Institute News

Research points to possible target to stop cancer stem cells

AuthorJessica Moore
Date

July 28, 2016

Fluorescently labeled stem cells

When you think of stem cells, you probably think of healing and regeneration—cells that can replace tissue lost to disease or injury. But tumors also arise from stem cells—a specific kind called cancer stem cells. Because these cells can divide indefinitely, while other cancer cells’ proliferation is more limited, therapies that get rid of them would eventually stop a tumor from growing, and from ever coming back.

Researchers in the laboratory of Dieter Wolf, MD, professor in the NCI-Designated Cancer Center, may have found a new way to do this, though in a roundabout way. While examining the function of two proteins found at high levels in tumors, they discovered that these factors are required for a type of metabolism that’s essential for cancer stem cells to survive.

“Our findings suggest that these components, eukaryotic initiation factors (eIFs) 3d and 3e, are novel targets for eliminating cancer stem cells,” said Wolf, senior author of the study, which was published in Cell Reports. “If we could find a way to turn these factors off, we could starve cancer stem cells.”

The details

eIF3d and eIF3e are part of the complex that initiates protein synthesis, also called translation. Specifically, they and other eIFs help bring the ribosome, which builds proteins by linking amino acids one by one, to messenger RNA, the molecules that carry the code the ribosome reads, specifying which amino acid should be added next.

Wolf’s team was interested in whether overproduction of eIF3d and eIF3e promotes cancer progression. To determine their function, they compared the amounts of all proteins made in cells lacking these factors to those in normal cells. A difference that stood out was in the levels of the protein complexes required to produce ATP, the cell’s energy currency, in mitochondria—eIF3d/e-deficient cells produced far lower amounts than normal.

“Cancer stem cells, unlike most tumor cells, rely on mitochondrial metabolism for energy,” Wolf explained. “Since tumor cells have much higher levels of eIF3d/e than normal cells, inhibiting those factors would preferentially block metabolism in cancer stem cells.

“Our results are somewhat surprising because eIF3 has long been thought to control the synthesis of all proteins. Instead, our data suggest that some parts of eIF3 selectively recruit certain mRNAs.”

Next steps

“We’re now examining how eIF3d/e affects cancer metabolism overall to see if these factors might be relevant to more than just cancer stem cells,” added Wolf. “Also, as a step towards advancing this research to the clinic, we’re designing screens to identify small molecule inhibitors of eIF3d/e.”

The paper is available online here.

Institute News

Sanford-Burnham presents at AACR April 19-22

Authorsgammon
Date

April 21, 2015

Header image

 

The American Association of Cancer Research (AACR) Annual Meeting, held April 18-22 in Philadelphia, will attract approximately 18,000 attendees from around the world. They are coming to hear from an outstanding roster of speakers, hundreds of live talks, and more than 6,000 proffered papers from scientists and clinicians around the world. This year’s theme, “Brining Cancer Discoveries to patients,” highlights the need to link laboratory discoveries to treatments for the purpose of finding cancer cures. Continue reading “Sanford-Burnham presents at AACR April 19-22”