Elevated
insulin levels have been associated with an increased
cancer risk as well as with aggressive and metastatic
cancer phenotypes characterized by a poor prognosis.
Insulin stimulates the proliferation, migration, and invasiveness of
cancer cells through diverse transduction pathways, including
estrogen signaling. As
G protein estrogen receptor 1 (GPER1) mediates rapid cell responses to
estrogens, we evaluated the potential of
insulin to regulate GPER1 expression and function in
leiomyosarcoma cancer cells (SKUT-1) and
breast cancer-associated fibroblasts (CAFs), which were used as a model system. We found that
insulin transactivates the GPER1 promoter sequence and increases the
mRNA and
protein expression of GPER1 through the activation of the PRKCD/MAPK1/c-Fos/AP1 transduction pathway, as ascertained by means of specific pharmacological inhibitors and gene-silencing experiments. Moreover, cell migration triggered by
insulin occurred through GPER1 and its main target gene CTGF, whereas the
insulin-induced expression of GPER1 boosted cell-cycle progression and the
glucose uptake stimulated by
estrogens. Notably, a positive correlation between
insulin serum levels and GPER1 expression was found in
cancer fibroblasts obtained from
breast cancer patients. Altogether, our data indicate that GPER1 may be included among the complex network of transduction signaling triggered by
insulin that drives cells toward
cancer progression.