Abstract
The GTPase Rac1 is a well-established master regulator of cell motility and invasiveness contributing to cancer metastasis. Dysregulation of the Rac1 signaling pathway, resulting in elevated motile and invasive potential, has been reported in multiple cancers. However, there are limited studies on the regulation of Rac1 in prostate cancer. Here, we demonstrate that aggressive androgen-independent prostate cancer cells display marked hyperactivation of Rac1. This hyperactivation is independent of P-Rex1 activity or its direct activators, the PI3K product PIP3 and Gβγ subunits. Furthermore, we demonstrate that the motility and invasiveness of PC3 prostate cancer cells is independent of P-Rex1, supporting the analysis of publicly available datasets indicating no correlation between high P-Rex1 expression and cancer progression in patients. Rac1 hyperactivation was not related to the presence of activating Rac1 mutations and was insensitive to overexpression of a Rac-GAP or the silencing of specific Rac-GEFs expressed in prostate cancer cells. Interestingly, active Rac1 levels in these cells were markedly reduced by elevations in intracellular calcium or by serum stimulation, suggesting the presence of an alternative means of Rac1 regulation in prostate cancer that does not involve previously established paradigms.
Highlights
Prostate cancer is the most frequently diagnosed malignancy in men in the United States aside from skin cancer, with an estimated 175,000 new cases in 2019, and the second leading cause of cancer-related deaths in men [1]
To further validate the P-Rex1 independence of Rac1 activation in prostate cancer cells, we examined the effect of the PI3K inhibitor BKM120 and gallein, an agent that disrupts Gβγ signaling
As a second approach to evaluate the role of intracellular calcium in small GTPase deactivation, we evaluated the effect of thapsigargin, a sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase (SERCA) pump inhibitor that promotes a significant elevation in intracellular calcium [44]
Summary
Prostate cancer is the most frequently diagnosed malignancy in men in the United States aside from skin cancer, with an estimated 175,000 new cases in 2019, and the second leading cause of cancer-related deaths in men [1]. The 5-year survival rate for patients with localized prostate cancer is. This is dramatically reduced to 30% in patients with metastatic prostate cancer [1]. Aggressive metastatic phenotypes are associated with androgen independence, resulting in resistance to androgen ablation or castration therapies (“Castration-Resistant Prostate Cancer” or CRPC). Prostate cancer cells that have acquired androgen independence have a significant propensity to metastasize. There is currently no treatment available to cure such androgen-independent prostate cancer, and a greater understanding of the mechanisms that drive CRPC is essential [2]
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