Oncogenic GNAQ/11-induced remodeling of the IP3/Calcium signaling pathway protects Uveal Melanoma against Calcium-driven cell death

Despite being considered a rare tumor, uveal melanoma (UVM) is the most common adult intraocular malignancy. With a poor prognosis and limited treatment options, up to 50% of patients develop metastases, primarily in the liver. A range of mutations and chromosomal aberrations with significant prognostic value has been associated with UVM pathogenesis. The most frequently mutated genes are GNAQ and GNA11, which encode the subunits of Gq proteins and are described as driver mutations that activate multiple signaling cascades involved in cell growth and proliferation. Directly downstream of Gq/11 activation, PLC{beta} engagement leads to sustained production of DAG and IP3. While the DAG/PKC/RasGRP3/MAPK signaling branch has been identified as an essential component of UVM unregulated proliferation, the role of IP3-mediated signals has been largely overlooked. Here, we demonstrate that, whilst maintaining Ca{superscript 2} homeostasis, UVM cells have developed a decoupling mechanism between IP3 and ER Ca{superscript 2} release by altering IP3 receptor (IP3R) expression. This correlation was observed in human UVM tumors, where IP3Rs were found to be downregulated. Critically, when IP3R3 expression was restored, UVM cells exhibited an increased tendency to undergo spontaneous cell death and became more sensitive to pro-apoptotic modulators of IP3R-mediated Ca{superscript 2} signaling, such as staurosporine and the Bcl2-IP3R disrupter peptide BIRD2. Finally, inhibition of the Gq/11 signaling pathway revealed that IP3R expression is negatively regulated by GNAQ/11 oncogenic activation. Hence, we demonstrated that by remodeling IP3R expression, GNAQ/11 oncogenes protect UVM cells against IP3-triggered Ca{superscript 2} overload and cell death. Therefore, the GNAQ/11 pathway not only drives proliferation through DAG activity but also provides a protective mechanism to evade IP3/Ca{superscript 2}-mediated cell death. These dual functions could potentially be exploited in novel combinatorial therapeutic strategies to effectively block UVM cell proliferation while simultaneously sensitizing them to cell death.