New study could help reduce pain in oral cancer patients

According to the researchers, calcium channels have been shown to contribute to cancer progression, but very few studies to date have examined the role of ORAI1 in not only cancer progression but also pain causation. “Our results show that the ORAI1 channel fuels the growth of oral cancer tumours and produces an abundance of molecules that, once secreted, interact with neurons resulting in an increased sensitivity to pain,” lead author Dr Ga-Yeon Son, a postdoctoral fellow in the Department of Molecular Pathobiology at NYU Dentistry, said in a press release.

The name “ORAI” pays homage to the Horae sisters who, according to Greek mythology, guarded the gates of heaven at Mount Olympus. Similarly, the researchers view the ORAI1 channel as the guardian of calcium entering the cells.

“These calcium channels can be a source of good or bad for cells,” said senior author Dr Rodrigo S. Lacruz, professor of molecular pathobiology at the university. “Calcium entering cells is necessary for many good things, but too much calcium for a long time has the opposite effect,” he explained.

Study results

In the study, the researchers analysed tissue samples obtained from both human oral cancer tumours and healthy tongues. They observed a significant upregulation of the ORAI1 gene, which is responsible for encoding the ORAI1 calcium channel, in the tumour samples. However, ORAI1 gene overexpression was not observed in the healthy tissue.

The researchers then examined human oral cancer cells and discovered that the activation of the ORAI1 channel, as opposed to other calcium channels, triggered a substantial influx of calcium into the cancer cells. This influx, in turn, led to an elevation in the levels of a calcium-dependent enzyme known as matrix metalloproteinase-1 (MMP-1), which is secreted from the cancer cells and is critically involved in carcinogenesis.

From left: Co-authors Prof. Rodrigo S. Lacruz and Dr Ga-Yeon Son. (Image: NYU)

After removing the ORAI1 gene from oral cancer cells in animal studies, the researchers noticed that tumours progressed more slowly and were less painful, which caused them to wonder whether the MMP-1 was the messenger relaying pain. They later discovered that the MMP-1-rich fluid surrounding oral cancer cells with ORAI1 induced an increase in action potentials, which are essential for transmitting pain signals.

“This gives us evidence that an abundance of MMP-1 may generate increased sensitivity to pain,” Prof. Lacruz explained.

Further experiments also showed that ORAI1 gene overexpression in non-invasive cells transformed the cells into invasive ones. Based on the findings, the researchers will now assess a novel drug delivery method that seeks to block the ORAI1 gene in order to test whether it can help prevent oral cancer progression and pain in patients.

The study, titled “The Ca²⁺ channel ORAI1 is a regulator of oral cancer growth and nociceptive pain”, was published on 5 September 2023 in Science Signaling.