How a Cellular ‘Engine’ Controls Constructing Blocks of DNA 

Northwestern Medicine scientists have uncovered a shocking hyperlink between a tiny mobile engine and the way in which most cancers cells construct the DNA they should proliferate, in accordance with a brand new examine published in Molecular Cell.  

The discovery may open the door to new therapies that starve tumors of their important constructing blocks, mentioned Issam Ben-Sahra, PhD, the Thomas D. Spies Professor of Genetic Metabolism and affiliate professor of Biochemistry and Molecular Genetics, who was senior creator of the examine. 

“Cancer cells have an altered metabolism. They use genes, such as oncogenes or tumor suppressor genes, to allow cells to grow and proliferate in an uncontrolled fashion,” Ben-Sahra mentioned. “In the field of cancer metabolism, we always try to understand how metabolic networks communicate with each other, how they signal to each other to control cell function and fate.” 

In the examine, Ben-Sahra and his collaborators targeted on an enzyme referred to as succinate dehydrogenase (SDH), a key a part of the mitochondria — the cell’s “power plants.” Investigators discovered that after they blocked SDH utilizing CRISPR-Cas9 gene enhancing or chemical medication, cells struggled to make purines, the molecules that type DNA and RNA. Without purines, cells can not multiply effectively. 

Investigators additionally noticed that when SDH is inhibited, the extent of succinate rises. This extra succinate interferes with one other enzyme, SHMT2, which often helps produce molecules wanted for purine meeting. With SHMT2 slowed down, the cell’s purine manufacturing stalls. 

However, blocking this course of doesn’t cease most cancers cells, investigators discovered. Instead, the most cancers cells change to a backup system often known as the purine salvage pathway, by which the cells recycle outdated purines to continue to grow. The examine investigators realized this adaptation could possibly be exploited: if each SDH and the salvage pathway are blocked on the similar time, most cancers cells would lose their capacity to construct DNA altogether. 

“When we inhibit SDH, it triggers the activation of the purine salvage pathway to compensate for the inhibition of the de novo pathway,” mentioned Ben-Sahra, who can be a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “Now the goal is to target SDH in combination with inhibition of the salvage pathway to prevent that compensation.” 

In cultured cells and in mice, this dual-targeted technique confirmed highly effective anti-tumor results, suggesting a brand new solution to assault cancers that rely closely on purine manufacturing. 

“Combining low doses of SDH inhibitor and low dose of salvage inhibitors, we can synergize and decrease tumor growth and proliferation,” Ben-Sahra mentioned. “The take-home message here is that succinate can control purine synthesis. That’s new knowledge.” 

The findings spotlight succinate not simply as a waste product of metabolism, however as a sign molecule that may reshape how cells construct the very foundations of life. The outcomes additionally counsel that reducing off most cancers’s provide strains at their supply could possibly be a promising new avenue for treating the illness. 

Next, Ben-Sahra mentioned he and his laboratory will take a look at their findings in cancers that includes SDH mutations. 

“The goal here is to see whether these mutant cancers, which have a high level of SDH, might be more sensitive to inhibition of the salvage pathway,” he mentioned.  

Mushtaq Nengroo, PhD, a postdoctoral fellow within the Ben-Sahra laboratory, was the primary creator of the examine. Marc Mendillo, PhD, affiliate professor of Biochemistry and Molecular Genetics, was co-senior creator of the examine. 

The examine was supported by grants from the National Institutes of Health (R01GM135587, R01GM143334, R35GM158171, R01GM144617, R01CA258833, R21ES035975, and R35GM137836). Additional funding was supplied by the LAM Foundation Established Investigator Award (LAM0151E01-22) and American Cancer Society Awards (DBG-23-1039959-01-TBE).