Moffitt researchers discover critical pathway for development of lymphoma

Newswise – TAMPA, Florida. — MYC proteins are important regulators of cancer cell growth, proliferation and metabolism through their ability to increase the expression of proteins involved in these processes. Dysregulation of MYC proteins occurs in more than half of all cancers and is associated with poor prognosis and patient outcomes. Many researchers have devoted significant effort to attempt to target MYC proteins as a therapeutic approach to treat cancer. However, this has been extremely difficult to date, and other complementary strategies are being explored.

In a New article in Blood Cancer Discovery, which was published concurrently with a presentation at the 2023 Annual Meeting of the American Association for Cancer Research, a team of Moffitt Cancer Center the researchers demonstrated a possible alternative approach. They showed that MYC activates a downstream pathway that chemically modifies a protein called eIF5A, and that inhibiting this modification process prevents the development and progression of lymphoma in mouse models.

“Our team hypothesized that instead of targeting MYC directly, it might be possible to inhibit its effects on cancer by targeting a protein downstream of the MYC effector protein that is also essential for cancer development,” said Shima Nakanishi, Ph.D., study leader. author and researcher Department of Tumor Biology in Moffit. “We have focused our efforts on the polyamine biosynthetic pathway which is involved in cell growth and survival and which is hyper-altered in many cancers.

The Moffitt team showed that MYC induces the expression of eIF5A and an enzyme called DHPS which modifies eIF5A with a unique amino acid called hypusine. The Moffitt researchers wanted to test whether this chemical modification of eIF5A is important for the development and maintenance of lymphoma. They conducted laboratory experiments with cell lines and mouse models and determined that hyposin-modified eIF5A is essential for the development of MYC-regulated lymphomas. When the researchers genetically or chemically blocked this modification by targeting eIF5A or DHPS, the development and progression of lymphoma was inhibited. Mechanically, they found that the hypusine-modified eIF5A was important for the production of proteins responsible for cell growth and DNA replication. This is the first study to show conclusively that this modification is important for the development of cancer.

“As activation of the hypusine circuit is a hallmark of MYC-induced tumors, the development of improved small molecule inhibitors of DHPS, or agents that bind to and block eIF5A-hypusine function, are attractive therapeutic strategies. to translate these findings into clinical practice,” said the study author. John Cleveland, Ph.D.director of the center and scientific director of Moffitt.

This study was supported by the National Cancer Institute (CA100603, CA241713, DK124906, DK060581 and P30 CA076292), Cortner-Couch Endowed Chair for Cancer Research at the University of South Florida School of Medicine, Diabetes Research Center (P30 DK020595) and Florida State funds.

About the Moffitt Cancer Center
Moffit is dedicated to a vital mission: to help prevent and cure cancer. The Tampa-based facility is one of 53 National Cancer Institute Designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s scientific excellence, multidisciplinary research, and solid training and education. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest honor. With more than 7,800 team members, Moffitt has an economic impact in the state of $2.4 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.organd follow the momentum on Facebook, Twitter, instagram And Youtube.

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