Activating a new mechanism to promote cell death could provide hope for better mesothelioma treatments, a Japanese study indicates.
The laboratory research was led by Miaki Uzu and Hiromi Sato of the Graduate School of Pharmaceutical Sciences at Chiba University.
The protein connexin, or Cx, is a key player in the cell-to-cell communication that is essential to maintaining cell functioning.
Cx forms channels, called gap junctions, that facilitate the passage of small molecules. A specific region in the Cx structure interacts with other proteins. These include the Bax protein, which promotes programmed cell death, or apoptosis.
Programmed cell death is a vital function. It rids the body of cells that are damaged or potentially dangerous. When that function is disrupted, cancer can occur.
Previous research that the Chiba University team conducted dealt with a cancer therapy’s ability to trigger apoptosis. The therapy, Sutent (sunitinib malate), prompted a Cx subtype known as Cx43 to trigger Bax-mediated programmed cell death in malignant mesothelioma cells.
The finding suggested that a combination of drugs focusing on Cx could become a new cancer treatment strategy. But the team had yet to identify the mechanism underlying Cx43-driven apoptosis.
So the researchers genetically engineered malignant mesothelioma cells to produce Cx43. When they treated the cells with Sutent, they produced more Bax. The team noted that the protein was predominantly located at — and caused the dysfunction of — mitochondria, a cell component responsible for energy production.
Sutent also increased levels of the protein JNK in the Cx43-engineered cells. JNK is a key modulator of cell-to-cell signaling, and it stabilizes Bax’s activity. Importantly, lowering levels of JNK suppressed Bax activation, the researchers found.
In addition, the scientists discovered that JNK and Bax were in close proximity in the cells, indicating they were interacting with each other. When the team eliminated Cx43 from the cells, JNK and Bax were no longer in proximity.
The study indicated that Cx43, JNK and Bax can act together to regulate programmed cell death.
In addition, “Bax expression level was correlated with the good responses to chemotherapy in patients with advanced gastric and breast tumors,” the researchers wrote. Together, the results suggest that therapies that promote the production of Cx and that target Bax could be a way to treat mesothelioma.
Although researchers expected Sutent to be an effective treatment for malignant mesothelioma, early results showed it had limited impact. Still, the team’s findings suggest that building therapies around Cx could lead to more effective cancer treatments.
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