Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

Laboratory of Calciomics and Systemic Pathophysiology (LCSP), Regional Centre for Biotechnology (RCB), Faridabad, Delhi-NCR, India
2CSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
3Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
*Correspondence: rajender.motiani@rcb.res.in

Our recently published study shows that a calcium channel “Orai3” regulates pancreatic cancer metastasis. Pancreatic cancer is one of the most lethal forms of cancers. The 5-year mean survival rate for pancreatic cancer patients is less than 10%. It is important to note that most of the pancreatic cancer related deaths are due to secondary metastasis to other organs of the body. However, the molecular players that regulate pancreatic cancer metastasis remain poorly appreciated. Therefore, aim of our research program is to identify and characterize novel targetable proteins that contribute to pancreatic cancer metastasis. In long run, this knowledge base would eventually help in better clinical management of pancreatic cancer.

Calcium (Ca2+) signaling plays a critical role in regulating hallmarks of cancer progression including cell proliferation, migration and apoptotic resistance. Ca2+ entry into the cells is mediated by several types of channels present on plasma membrane. However, the role of Ca2+ channels in driving pancreatic cancer progression is inadequately understood. Hence, we started examining the contribution of Ca2+ channels in regulating pancreatic cancer. We studied expression analysis of Ca2+ channels in publicly available pancreatic cancer patients datasets. We observed that the expression of Orai3, a highly Ca2+ selective channel, is higher in pancreatic cancer samples in comparison to normal pancreas. Moreover, our analysis suggested that greater Orai3 expression is associated with less mean survival time of pancreatic cancer patients. Thereby implicating that higher Orai3 expression leads to poor prognosis in pancreatic cancer patients.

We next carried out a battery of independent experiments to demonstrate that Orai3 is responsible for enhanced Ca2+ influx into pancreatic cancer cells. Further, we performed numerous assays on pancreatic cancer cells and observed that Orai3 regulates tumorigenic properties of pancreatic cancer cells. We found that Orai3 regulates both proliferation and migration of pancreatic cancer cells. Most importantly, we evaluated the role of Orai3 in driving pancreatic cancer progression and metastasis in a mice model. We performed injections of human pancreatic cancer cells expressing either high or low levels of Orai3 in immune-compromised mice. Pancreatic cancer metastasis was drastically decreased in the cells having lower Orai3 expression. These in vivo studies demonstrate a critical role of Orai3 in pancreatic tumour growth and secondary metastasis. Taken together, our data implies that Orai3 is a critical regulator of pancreatic cancer progression and metastasis.

Our study for the first-time reports that Orai3 drives pancreatic cancer metastasis. Further, higher Orai3 expression leads to poor survival rates in pancreatic cancer patients. Notably, majority of pancreatic cancer associated deaths are due to secondary metastasis. Therefore, our study infers that Orai3 could be a potential therapeutic target for managing pancreatic cancer metastasis.
Reference:

Arora S, Tanwar J, Sharma N, Saurav S and Motiani RK (2021). Orai3 regulates pancreatic cancer metastasis by encoding a functional store operated calcium entry channel. Cancers 2021 Nov 25;13(23):5937. doi: 10.3390/cancers13235937.