Compounds that inhibit septin and their chemical derivatives are intriguing anti-cancer drug candidates!

Researchers from the University of Texas Southwestern Medical Center note in a new study that cell membrane protrusions called follicles (blebs) normally signal the end of life for healthy cells, but the opposite is true for melanoma cells, which activate these protrusions to help them survive and spread. These findings may lead to new therapies for melanoma and other malignancies. The results were published online on 1 March 2023 in the journal Nature in an article titled “Blebs promote cell survival by assembling oncogenic signalling hubs.”

According to Dr. Gaudenz Danuser, co-corresponding author of the paper and chair of the Department of Bioinformatics at the University of Texas Southwestern Medical Center, “There is an old saying in biology that form follows function. In contrast, we have reversed this concept on its head here. By altering the morphology, we demonstrate that the chemical processes within the cell that regulate its function can be altered.” Andrew D. Weems, Ph.D., of Danuser’s lab, is the second co-corresponding author of the paper.

Dr. Weems explained that healthy cells isolated from larger tissues will almost certainly die unless they can reattach within hours, a process known as anoikis. However, a characteristic of malignant tumor cells is that once they are isolated from tumor tissue, they remain viable indefinitely, allowing them to survive and migrate to other parts of the body to form metastatic tumors. At the time of isolation, they form follicles indefinitely, whereas healthy cells can only form follicles for approximately one hour after detaching from their tissue of origin.

Previous research in the Danuser laboratory demonstrated that under adverse conditions, follicles accumulate proteins that promote cell survival. However, it has been unknown whether these proteins aid cancer cells in avoiding loss-of-nest apoptosis and how they are contained in the follicles.

These previous studies have shown that follicles attract a family of proteins called septin, which are attracted to areas of high cell membrane curvature like those found in follicles and form molecular scaffolds that provide a framework for protein interactions. “Here,” Dr. Weems said, “the septin scaffold contains Ras proteins, which regulate cell survival in about one in five cancers mutations occur.”

When these authors treated melanoma cells with a septin-inhibiting compound called forchlorfenuron (FCF), septin could no longer act as a scaffold for the Ras protein, resulting in these tumor cells being unable to maintain the chemical reactions that allow them to survive. Thus, when they are separated from other cells, they die, the same fate as healthy cells. In contrast, when they introduce mutations that cause healthy cells to take longer than normal to form follicles, these cells become as resistant to loss-of-nest apoptosis as cancer cells, even though these cells do not carry the oncogenic Ras mutation.

These results support Dr. Danuser’s hypothesis that “oncogenic mutations” require additional cellular arrangements to exert their malignant effects. However, encouraging certain cellular configurations alone can provide otherwise healthy cells the ability to produce cancer without the need for mutations. This sheds significant new light on the origins of cancer.

Dr. Weems added that scientists had tried to block Ras activity for decades with not much success. Ras itself is assumed to be untargetable by drugs because of its unusual molecular structure. In addition, he said, it’s possible to do the same thing by targeting septin, which would eliminate cancer cells’ capacity to resist apoptosis in the lost nest and make them more amenable to other therapies like chemotherapy, radiation, and immunotherapy.

According to Dr. Weems, “FCF has been used as an agricultural chemical in the United States for nearly 20 years, and data from the United States Environmental Protection Agency indicate that it has low toxicity to humans.” Potentially useful new anti-cancer drugs include this septin-inhibiting molecule and its chemical analogs.

Comments are closed