Inhibition of Cdc42 and Rac1 activities in pheochromocytoma, the adrenal medulla tumor

Abstract

Altered Rho GTPase signaling has been linked to many types of cancer. As many small G proteins, Rho GTPases cycle between an active and inactive state thanks to specific regulators that catalyze exchange of GDP into GTP (Rho-GEF) or hydrolysis of GTP into GDP (Rho-GAP). Recent studies have shown that alteration takes place either at the level of Rho proteins themselves (expression levels, point mutations) or at the level of their regulators, mostly RhoGEFs and RhoGAPs. Most reports describe Rho GTPases gain of function that may participate to the tumorigenesis processes. In contrast, we have recently reported that decreased activities of Cdc42 and Rac1 as well as decreased expression of 2 Rho-GEFs, FARP1 and ARHGEF1, correlate with pheochromocytomas, a tumor developing in the medulla of the adrenal gland (Croise et al., Endocrine Related Cancer, 2016). Here we highlight the major evidence and further study the correlation between Rho GTPases activities and expression levels of ARHGEF1 and FARP1. Finally we also discuss how the decrease of Cdc42 and Rac1 activities may help human pheochromocytomas to develop and comment the possible relationship between FARP1, ARHGEF1 and the 2 Rho GTPases Cdc42 and Rac1 in tumorigenesis.

Hormones Secretion and Rho GTPases in Neuroendocrine Tumors

“…For example, in pheochromocytoma, a NET arising from chromaffin cells of the adrenal medulla, we observed that the activity of Rac1 and Cdc42 was inhibited while their relative expression remained unchanged compared to non-tumor tissue [57]. In this study, we further showed that the inhibition of Rac1 and Cdc42 activities in human pheochromocytomas was directly correlated to reduced expression of the GEFs ARHGEF1 and FARP1, respectively [57,58]. In the very aggressive SDHB-pheochromocytoma, microRNAs controlling the Rho GAP ARHGAP18 expression are specifically overexpressed [59].…”

Melatonin Protects Cardiomyocytes from Oxygen Glucose Deprivation And Reperfusion-Induced Injury by Inhibiting Rac1/JNK/Foxo3a/Bim Signaling Pathway

“…Previous studies have demonstrated that increased levels of active myocardial Rac1 renders the heart susceptible to I/R injury [11,24,25]. As other Rho GTPases, Rac1 cycle between an active and inactive state thanks to speci c regulators that catalyze exchange of GDP into GTP (Rac1-GEF) or hydrolysis of GTP into GDP (Rac1-GAP) [26,27]. It has been demonstrated that the activity of Rac1 was regulated by speci c GEF or GAP in different cell settings [26,27].…”

“…As other Rho GTPases, Rac1 cycle between an active and inactive state thanks to speci c regulators that catalyze exchange of GDP into GTP (Rac1-GEF) or hydrolysis of GTP into GDP (Rac1-GAP) [26,27]. It has been demonstrated that the activity of Rac1 was regulated by speci c GEF or GAP in different cell settings [26,27]. Thus, it will be worthwhile to investigate which cardiomyocyte-speci c GAP mediates melatonin-induced Rac1 inactivation in our system.…”

Melatonin protects H9c2 cardiomyoblasts from oxygen‐glucose deprivation and reperfusion‐induced injury by inhibiting Rac1/JNK/Foxo3a/Bim signaling pathway

“…Consistently, our study demonstrated that melatonin‐induced Rac1 inactivation contributed to the protective effect of melatonin against OGD/R‐induced injury of H9c2 cardiomyoblasts. Like other Rho GTPases, Rac1 also cycles between an active and inactive state thanks to specific regulators that catalyze exchange of GDP into GTP (Rac1‐GEF) or hydrolysis of GTP into GDP (Rac1‐GAP) (Aslan, 2019; Croise et al, 2017). It has been demonstrated that the activity of Rac1 was regulated by specific GEF or GAP in different cell settings (Aslan, 2019; Croise et al, 2017).…”