Abstract
Ran is a nucleocytoplasmic shuttle protein that is involved in cell cycle regulation, nuclear-cytoplasmic transport, and cell transformation. Ran plays an important role in cancer cell survival and cancer progression. Here, we show that, in addition to the nucleocytoplasmic localization of Ran, this GTPase is specifically associated with the plasma membrane/ruffles of ovarian cancer cells. Ran depletion has a drastic effect on RhoA stability and inhibits RhoA localization to the plasma membrane/ruffles and RhoA activity. We further demonstrate that the DEDDDL domain of Ran is required for the interaction with serine 188 of RhoA, which prevents RhoA degradation by the proteasome pathway. Moreover, the knockdown of Ran leads to a reduction of ovarian cancer cell invasion by impairing RhoA signalling. Our findings provide advanced insights into the mode of action of the Ran-RhoA signalling axis and may represent a potential therapeutic avenue for drug development to prevent ovarian tumour metastasis.
Highlights
Ran is a nucleocytoplasmic shuttle protein that is involved in cell cycle regulation, nuclearcytoplasmic transport, and cell transformation
RhoA is one of the most-studied Rho GTPase, it is activated by guanine-nucleotide exchange factors (GEFs) and is inactivated by guanine-nucleotide dissociation inhibitors (GDIs), which prevent its interaction with the plasma membrane (PM), but not necessarily with downstream targets[11]
We examined the effect of Ran depletion by RNA interference (RNAi) in two aggressive Epithelial ovarian cancer (EOC) cell lines (TOV-112D and TOV-1946) derived in our laboratory[20,21] (Fig. 1a; Supplementary Fig. 1a)
Summary
Ran is a nucleocytoplasmic shuttle protein that is involved in cell cycle regulation, nuclearcytoplasmic transport, and cell transformation. We show that, in addition to the nucleocytoplasmic localization of Ran, this GTPase is associated with the plasma membrane/ruffles of ovarian cancer cells. The knockdown of Ran leads to a reduction of ovarian cancer cell invasion by impairing RhoA signalling. We have demonstrated that the small GTPAse Ran (Ras-related nuclear protein) is strongly associated with EOC progression, poor overall survival, and a high risk of recurrence[5,6]. RhoA GTPase coordinately regulates multiple aspects of tumor cell invasion[15], and its expression is significantly associated with poor tumor differentiation and advanced stages of ovarian cancer[16]. Our findings describe a signaling pathway involving Ran that regulates EOC invasion through RhoA GTPase activity and may lead to alternative therapeutic strategies for ovarian cancer
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