Credit: Ed Uthman
Researchers say they’ve discovered how the protein STAT3 interferes with an antitumor mechanism in cells, thereby promoting the growth of lymphoma and other cancers.
The group made their discovery using the Epstein-Barr virus (EBV) as a tool to investigate cancer development.
“Our findings add to the short list of known mechanisms by which a key cellular antitumor barrier is breached by STAT3 prior to cancer development,” said Sumita Bhaduri-McIntosh, MD, PhD, of Stony Brook University School of Medicine in New York.
“Because STAT3 interferes with this innate antitumor mechanism in cells, the opposite occurs when blood cells are infected in the lab with the cancer-causing virus EBV, and the cells continue to divide—a necessary step in cancer development.”
Dr Bhaduri-McIntosh and her colleagues described their research in PNAS.
The team explained that STAT3 inhibits a cancer-suppressing cellular activity called the DNA damage response (DDR). Normally, this response pauses cell division, allowing for the repair of damaged DNA.
But this study showed that EBV not only causes DNA damage when it infects and replicates in cells; it also activates and increases STAT3 expression. This starts a chain reaction that leads to an “un-pause” in cell division, thereby promoting cell proliferation. This, in combination with other pro-proliferative effects of the virus, can lead to cancers.
The researchers found that DDR does detect replication stress-associated DNA damage resulting from EBV infection. But signaling downstream of ATR proteins is impaired by STAT3. And this leads to relaxation of the intra-S phase checkpoint of the cell cycle.
STAT3 interrupts signaling from ATR to the protein Chk1 by promoting the loss of Claspin, a protein that assists ATR to phosphorylate Chk1. The loss of Claspin, which facilitates cell proliferation, is mediated by caspase 7.
Previous research suggested that STAT3 and Chk1 are potential targets for cancer therapies. Dr Bhaduri-McIntosh’s team said their results provide new insight into anticancer drug development because they reveal a mechanistic link between these 2 proteins.
Dr Bhaduri-McIntosh emphasized that, because STAT3 is involved in most cancers, her group’s findings could potentially impact the prevention or treatment of several types of cancer—something her lab is investigating.
