Gasdermine E (GSDME) is an important regulator of cell death which is suppressed in various types of cancers. Researchers at Sidney Kimmel Cancer center recently discovered that the pore-forming protein acts through multiple pathways, targeting both cellular and mitochondrial membranes to mediate cell lysis and mitochondrial apoptosis, respectively. Their study, published in Nature Communications on April 11, outlines strategies to restore GSDME function to cause cancer cells to self-destruct.
As normal cells transform into cancerous cells they undergo numerous internal changes and environmental stresses, including excessive replication, DNA damage, and increased oncogene signaling. These stresses typically signal the cell to self-destruct, in order to prevent them from getting out of control.
Among the proteins that regulate and carry out these suicidal programs is GSDME. GSDME forms pores in the extracellular membrane, causing cells to leak their contents and burst through osmotic pressure. In addition, researchers report that GSDME also targets mitochondrial membranes, destroying the energy production of the cell and releasing cytochrome C to activate downstream apoptosis pathways. This secondary apoptotic mechanism is a powerful accelerator of cell suicide.
However, in some cases cancer cells escape suicide by downregulating GSDME. “GSDME is reported to be downregulated in breast, gastric and colorectal tumors, … and may represent an advantageous adaptation for tumor survival,” said lead author Emad Alnemri, Ph.D., the Thomas Eakins endowed Professor of Biochemistry and Molecular Biology at Sidney Kimmel Cancer Center—Jefferson Health (SKCC). Indeed, in cell lines and mouse models they find that augmenting GSDME expression delays tumor formation and suppresses tumor growth. “We found that cells with GSDME grow less and are actually more susceptible to death,” says Alnemri. “They don’t form tumors as well either, while the cells that lack this protein form bigger tumors and kill the mice much faster.” This may make GSDME a good candidate biomarker to identify aggressive, fast growing tumors for more aggressive treatments.
Restoring GSDME expression and its tumor suppressive effects may be possible with currently available treatments, particularly for patients with blood cancers, Alnemri reports. The researchers noted that glucocorticoids upregulate GSDME in T-lymphoblastic leukemia cells, likely contributing to their efficacy as anti-cancer agents. “Glucocorticoids are considered the cornerstone for treatment of lymphoid cancers, because of their ability to induce growth arrest and apoptosis,” said Alnemri. GSDME expression may therefore serve as in important biomarker for glucocorticoid-response, in lymphoid malignancies and possible other cancers.
In addition, GSDME activity might be augmented with other drugs, like kinase inhibitors. Cellular kinases like PLK1 are essential regulators of cellular proliferation and cell death that can drive cancer growth when they malfunction. Alnemri found that these kinases may prevent cancer cell death by phosphorylating GSDME, which causes a conformational change that eliminates its pore-formation capabilities.
“Our studies reveal that phosphorylation of T6 in GSDME … appears to be an important regulatory mechanisms to inhibit pore-forming functions,” said Alnemri. “If PLK1 can directly or indirectly phosphorylate GSDME, then this may inhibit pore forming activity… during oncogenesis to prevent cell death.” Pharmaceuticals that block kinases may therefore restore GSDME-mediated apoptosis and limit cancer growth. Dozens of such kinase inhibitors are already FDA-approved as anti-cancer treatments, but further research is required to determine which of these might be effective in the context of GSDME activity.