The RhoA dependent anti-metastatic function of RKIP in breast cancer

Abstract

Raf-1 kinase inhibitor protein was initially discovered as a physiological kinase inhibitor of the MAPK signaling pathway and was later shown to suppress cancer cell invasion and metastasis. Yet, the molecular mechanism through which RKIP executes its effects is not completely defined. RhoA has both a pro- and anti-metastatic cell-context dependent functions. Given that Rho GTPases primarily function on actin cytoskeleton dynamics and cell movement regulation, it is possible that one way RKIP hinders cancer cell invasion/metastasis is by targeting these proteins. Here we show that RKIP inhibits cancer cell invasion and metastasis by stimulating RhoA anti-tumorigenic functions. Mechanistically, RKIP activates RhoA in an Erk2 and GEF-H1 dependent manner to enhance E-cadherin membrane localization and inhibit CCL5 expression.

The Role of RKIP in the Regulation of EMT in the Tumor Microenvironment

“…Both RKIP and E-cadherin are tumor suppressors, and as such, there has been shown a positive correlation between the two, with both having decreased expression in cancer as invasion and metastasis increased [ 184 ]. RKIP in addition to expression correlations, also has a regulatory effect on E-cadherin, acting as an upstream activator [ 185 ]. In particular, in RKIP knockout studies, RKIP has been shown to activate RhoA, a negative regulator of breast cancer, which in turn, stabilizes E-cadherin in adherens junctions and regulates E-cadherin localization to the membrane [ 185 ].…”

“…RKIP in addition to expression correlations, also has a regulatory effect on E-cadherin, acting as an upstream activator [ 185 ]. In particular, in RKIP knockout studies, RKIP has been shown to activate RhoA, a negative regulator of breast cancer, which in turn, stabilizes E-cadherin in adherens junctions and regulates E-cadherin localization to the membrane [ 185 ]. RKIP regulates E-cadherin through Erk2 in the MEK/ERK pathway as well since RKIP inhibits the activation and phosphorylation of Erk2 [ 185 ].…”

“…In particular, in RKIP knockout studies, RKIP has been shown to activate RhoA, a negative regulator of breast cancer, which in turn, stabilizes E-cadherin in adherens junctions and regulates E-cadherin localization to the membrane [ 185 ]. RKIP regulates E-cadherin through Erk2 in the MEK/ERK pathway as well since RKIP inhibits the activation and phosphorylation of Erk2 [ 185 ]. Erk2 is a regulator of RhoA (and by downstream association E-cadherin) because Erk 2 disrupts the RhoA activator GEF-H1 [ 185 ].…”

“…RKIP regulates E-cadherin through Erk2 in the MEK/ERK pathway as well since RKIP inhibits the activation and phosphorylation of Erk2 [ 185 ]. Erk2 is a regulator of RhoA (and by downstream association E-cadherin) because Erk 2 disrupts the RhoA activator GEF-H1 [ 185 ]. E-cadherin could also be associated with RKIP through the other pathways that RKIP regulates such as NF-kB, which is activated in response to RKIP loss, which has an inverse relationship with E-cadherin, but more research would need to focus on the mechanism of such interaction if one exists [ 186 ].…”

Dahuang—Taoren, a botanical drug combination, ameliorates adenomyosis via inhibiting Rho GTPases

“…It has been confirmed that the activation of RhoA and Rac1 enhanced the migration of colorectal Frontiers in Pharmacology frontiersin.org cancer (Xie et al, 2021) (Wufuer et al, 2021). Other researchers have found that inhibition of Cdc42 was responsible for the suppression of invasion ability in lung cancer (Li et al, 2021), while the reduced RhoA had an anti-metastatic function on breast cancer (Kalpana et al, 2021). Further research suggests that Rho GTPases directly affect the plasticity of cells and promote cell movement by remodeling the cytoskeleton.…”