Just as penguins huddle together to survive cold temperatures, cells huddle together to resist proteotoxic stressors, that is, protein-damaging environmental stressors such as high temperatures, viral infections, and certain anticancer medications. This finding emerges from a study of a heat shock factor 2 (HSF2), which has long been known to be expressed at higher levels during prolonged proteotoxicity, and to play a role in preventing stress-induced protein misfolding. HSF2, it turns out, also maintains cell-cell adhesion.
HSF2 maintains cell-cell huddling through an intermediary: the cadherin protein. When cells are studded with lots of cadherin, cell adhesion is maintained, but when cadherin is sparse, cells may slip away from each other, and die. And cadherin tends to become sparse if HSF2 is lacking.
This was one of the conclusions made by a research team working under the leadership of Lea Sistonen, professor of cellular and molecular biology at Åbo Akademi University. The results of their research were recently published in Cell Reports, in an article entitled, “Heat Shock Factor 2 Protects against Proteotoxicity by Maintaining Cell-Cell Adhesion.”
The researchers were surprised by the findings because the molecules they studied are usually linked with other cellular functions.
“Our results show, for the first time, that the contacts between cells, known as cell adhesion, are essential for cells to survive stress. The findings also suggest that impaired cell adhesion may sensitize cancer cells to drugs that damage cell proteins and cause stress,” Sistonen explained.
“Strikingly, our RNA sequencing (RNA-seq) analyses revealed that impaired viability of HSF2-deficient cells is not caused by inadequate induction of molecular chaperones but is due to marked downregulation of cadherin superfamily genes,” the article’s authors wrote. “We demonstrate that HSF2-dependent maintenance of cadherin-mediated cell-cell adhesion is required for protection against stress induced by proteasome inhibition.”
In other words, HSF2 contributes to protecting cells against stress by regulating those genes that mediate cell adhesion contacts.
This finding was obtained by studying, among other things, how cancer cells respond to certain commonly used anticancer drugs. Cancer cells with impaired cell adhesion contacts were significantly less successful in surviving the drug treatment than the cells showing intact cell adhesion.
“Cell-to-cell contacts are essential for normal tissue functioning and mechanisms,” explained Sistonen. “Cancer cells are known to utilize these contacts to form aggressive tumors and metastases. Our results show, indeed, that cancer cells become more vulnerable to drug treatment, when their cell contacts are weakened.
“Cell adhesion contacts are mediated by proteins known as cadherins, which serve as the source of message chains regulating cell death, but understanding of the molecular basis for these processes calls for further research. Individual differences in these particular cell processes may partly explain why certain drugs work effectively for some patients but not for others.”