RGS16 Inhibits Breast Cancer Cell Growth by Mitigating Phosphatidylinositol 3-Kinase Signaling

Abstract

Aberrant activity of the phosphatidylinositol 3-kinase (PI3K) pathway supports growth of many tumors including those of breast, lung, and prostate. Resistance of breast cancer cells to targeted chemotherapies including tyrosine kinase inhibitors (TKI) has been linked to persistent PI3K activity, which may in part be due to increased membrane expression of epidermal growth factor (EGF) receptors (HER2 and HER3). Recently we found that proteins of the RGS (regulator of G protein signaling) family suppress PI3K activity downstream of the receptor by sequestering its p85␣ subunit from signaling complexes. Because a substantial percentage of breast tumors have RGS16 mutations and reduced RGS16 protein expression, we investigated the link between regulation of PI3K activity by RGS16 and breast cancer cell growth. RGS16 overexpression in MCF7 breast cancer cells inhibited EGF-induced proliferation and Akt phosphorylation, whereas shRNA-mediated extinction of RGS16 augmented cell growth and resistance to TKI treatment. Exposure to TKI also reduced RGS16 expression in MCF7 and BT474 cell lines. RGS16 bound the amino-terminal SH2 and inter-SH2 domains of p85␣ and inhibited its interaction with the EGF receptor-associated adapter protein Gab1. These results suggest that the loss of RGS16 in some breast tumors enhances PI3K signaling elicited by growth factors and thereby promotes proliferation and TKI evasion downstream of HER activation.

Calcium Efflux Activity of Plasma Membrane Ca2+ ATPase-4 (PMCA4) Mediates Cell Cycle Progression in Vascular Smooth Muscle Cells

“…Rgs16 overexpression in MCF7 breast cancer cells inhibits EGFR-mediated proliferation and Akt phosphorylation, whereas shRNA-mediated extinction of Rgs16 augments cell growth (44). Transient as well as stable Rgs16 expression in CHO cells can attenuate IP3 production and p38 MAPK activation by platelet-activating factor receptor (45).…”

Regulator of G Protein Signaling 6 (RGS6) Induces Apoptosis via a Mitochondrial-dependent Pathway Not Involving Its GTPase-activating Protein Activity

“…In fact, we are aware of only two reports in which RGS proteins have been linked to changes in cell proliferation, i.e. RGS17 was found to stimulate growth of lung cancer cells (31) and RGS16 was found to inhibit epidermal growth factor receptor-stimulated growth of breast cancer cells by binding to a subunit of PI3K (32), an activity of RGS16 not involving G proteins. Likewise, a single report by Dulin et al (33) showed that expression of RGS3T in CHO cells increased the number of TUNEL-positive cells observed in response to serum withdrawal.…”

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

“…Considering the complex signaling downstream of G-protein subunits including ERK1/2, phosphoinositide 3-kinase (PI3K), and adenylate cyclases, the downregulation of Rgs16 by increased NRAS could serve as another strong enhancer in MPNST tumorigenesis. The loss of Rgs16 has been reported in some breast cancers, which facilitated the PI3K signaling (25).…”