By Rehma Ali
A groundbreaking study conducted by researchers at NYU College of Dentistry has unveiled the pivotal role of the ORAI1 calcium channel in the proliferation of oral cancer and the generation of debilitating pain. This discovery marks a potential turning point in oral cancer treatment, offering new avenues to combat the disease's progression and alleviate the suffering of patients.
Unlocking the Secrets of ORAI1
ORAI calcium channels, named after the three sisters in Greek mythology who guarded the gates of heaven at Mount Olympus, act as essential gatekeepers, regulating the influx of calcium into cells. While calcium is essential for numerous cellular processes, an excessive and prolonged influx can have detrimental effects.
Although calcium channels have been linked to various cancer types and their progression, limited studies have explored the role of ORAI1 in cancer and associated pain. This groundbreaking research, published in Science Signaling, bridges this gap, shedding light on the profound impact of the ORAI1 channel in the context of oral cancer.
ORAI1: A Key Driver of Oral Cancer
The study began by analyzing tissue samples from human oral cancer tumors and healthy tongues. The researchers observed a significant overexpression of the ORAI1 gene, responsible for creating the ORAI1 calcium channel, in the tumor tissue but not in healthy tissue.
Further experiments with human oral cancer cells confirmed that the activation of the ORAI1 calcium channel led to a substantial influx of calcium into cancer cells. This influx triggered the production of a calcium-dependent enzyme called matrix metalloprotease 1 (MMP1), which is secreted from cancer cells. MMP1 is abundantly found in multiple cancer types, including oral cancer, where its overexpression is associated with metastasis and poor prognosis.
ORAI1 Inhibition: Slowing Cancer Growth and Pain Relief
To determine the impact of ORAI1 in oral cancer progression, the researchers conducted animal studies, removing the ORAI1 gene from oral cancer cells. The results were remarkable, as tumors in mice lacking the ORAI1 gene grew more slowly and caused less pain.
These findings raised intriguing questions about the mechanism through which MMP1 might mediate pain. Collaborating with NYU Pain Research Center scientists, the team examined the levels of MMP1 in the fluid surrounding oral cancer cells. They discovered that cells without the ORAI1 gene secreted less MMP1 into the surrounding fluid. When this fluid was exposed to neurons from the trigeminal ganglia, responsible for pain transmission in oral cancer, it elicited a weaker response compared to the MMP1-rich fluid from cells with ORAI1.
This crucial evidence suggests that an excess of MMP1 may heighten pain sensitivity in oral cancer patients.
Future Prospects: Targeting ORAI1
Several FDA-approved drugs are known to block the ORAI1 calcium channel. While they have not yet been tested in the context of oral cancer, future studies will explore the possibility of loading nanoparticles with ORAI1-blocking drugs for precise delivery into animal models' tongues. This approach holds promise for halting oral cancer progression and providing relief from the excruciating pain experienced by patients.
Rajesh Khanna, director of the NYU Pain Research Center and a co-author of the study, remarked, "In light of the ongoing opioid crisis, our study paves the way for validating novel pain treatments in oral cancer." He added, "Ultimately, our hope is that targeting the ORAI1 channel in oral cancer can prevent or delay the progression from oral epithelial dysplasia to oral cancer tumors and concurrently alleviate the pain burden experienced by oral cancer patients."
The research received support from various institutes, including the National Institute of Dental and Craniofacial Research, National Institutes of Health HEAL Initiative, National Institute of Neurological Disorders and Stroke, and National Institute on Drug Abuse.
