According to Cornell’s Ithaca campus researchers, aggressive lymphomas known as diffuse large B cells lymphomas (DLBCLs), have a critical metabolic vulnerability. This vulnerability can be exploited in order to make the cancers starve. The study was published in Blood Cancer Discovery. It showed that ATF4, a protein that regulates the activities of hundreds more genes, plays a crucial role in the rapid growth of DLBCLs.
Scientists discovered that silencing ATF4 within DLBCL cells essentially fools them into starving themselves and slows their growth. Furthermore, targeting ATF4 together with a closely related metabolic proteins, SIRT3, further enhances this cancer-killing effect. “ATF4 represents a crucial and exploitable weakness in DLBCLs – and one that they seem to share regardless of the particular genetic mutations that cause them,” said Dr Ari Melnick (study co-senior author) and a member of Weill Cornell Medicine’s Sandra and Edward Meyer Cancer Center.
The study’s other co-senior authors are Dr Hening Li, a professor in Cornell University’s Department of Chemistry and Chemical Biology and a Howard Hughes Medical Institute investigator. Lymphomas, which are blood cancers, usually arise from immune cells like B cells. The vast majority of lymphomas in the United States are non-Hodgkin Lymphomas. DLBCLs account roughly for a third, or approximately 25,000 cases per annum.
DLBCLs can grow quickly and are aggressive. Despite many advances in lymphoma treatments in recent decades, around 40% of cases are still untreated. This is a stark reminder of the need to develop new treatment strategies. Dr Melnick, Professor Lin, and their collaborators set out to study SIRT3, which is found in mitochondria, tiny fuel reactors that burn oxygen in our cells, and are essential for powering all cellular activities.
In a study published in 2019, the researchers discovered that SIRT3 is a strong support for DLBCL survival and growth. It speeds up biochemical reactions that make the molecular building blocks cell need to proliferate. In the new study, the researchers explored further how SIRT3 promotes DLBCL growth and found that one of the important ways it does this is by increasing the production of another metabolism-influencing protein, ATF4.
Their experiments showed that SIRT3, which boosts DLBCL metabolism and reduces the levels of amino acid cells use to create proteins and fuel their growth, is a key component of SIRT3. This reduces the amount of amino acids that cells use to make proteins and fuel their growth. It also activates ATF4, which further supports DLBCLs malignant proliferation. In 2019, Dr Melnick, Dr Lin and Dr Lin created a selective SIRT3 inhibit and demonstrated that it kills DLBCL-cells regardless of their cancer-driving mutations.
Researchers have shown that SIRT3 inhibition can result in the accumulation specific amino acids. These are produced by the cells’ ability to cannibalize their own proteins. This causes DLBCL cells to behave as if they have adequate nutrition, which in turn leads to paradoxical suppressions of ATF4 production. To further harness this effect for therapeutic purposes, the investigators tested a compound that blocks ATF4 activation and found similar results in DLBCL cell lines.
Additionally, they discovered that simulating the blockers of ATF4 with SIRT3 has a remarkable lymphoma-killing effect. This is much stronger than either blocker by itself. Combining ATF4 inhibitors with SIRT3 inhibitors is a promising strategy to fight DLBCLs. “One of my favorite things about this study is how it shows how nutrient circumstances, in principle even from patients, can profoundly impact cancer-cell activity,” Dr Meng LI, the study’s first author, said. She is also an instructor of cancer genomics in medicine at Weill Cornell Medicine.
The team is currently conducting more experiments to determine the best way to target SIRT3-ATF4 to treat DLBCLs. “My lab has been researching sirtuins since more than ten years. However, this study revealed some interesting connections between SIRT3, metabolism and nutrient/stress sensing. Dr Lin said that they are excited to explore the potential for this finding to be translated into treatment of lymphoma. (ANI)
(This story was not edited by Devdiscourse staff. It is generated automatically from a syndicated feed.