IGF1-induced AKT phosphorylation and cell proliferation are suppressed with the increase in PTEN during luteinization in human granulosa cells

Abstract

Granulosa cells proliferate and then undergo differentiation; an inverse relationship between these processes is observed during terminal follicular growth. During terminal follicular growth and initial luteinization, there is a necessary transition of granulosa cells to a less proliferative and highly steroidogenic form in response to LH. Although the expression of several molecules has been reported to be up-regulated by LH, proliferation/differentiation transition is not fully understood. Here, we show that the expression of a tumor suppressor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was induced with human chorionic gonadotropin (hCG) treatment in human luteinized granulosa cells. Pretreatment with hCG attenuated insulin-like growth factor (IGF)-1-induced phosphorylation of AKT and cell proliferation, not phosphorylation of ERK1/2. Moreover, suppression of hCG-induced PTEN expression with siRNA increased AKT phosphorylation and cell proliferation in response to IGF1. We also demonstrate that a PI3K inhibitor, LY294002, not a MEK inhibitor, PD98059, inhibited IGF1-induced cell proliferation. In conclusion, PTEN induced to express by hCG in luteinized granulosa cells that inactivates AKT, not ERK, and attenuates IGF1-induced cell proliferation. PTEN expression may be a trigger for proliferation/differentiation transition in human granulosa cells.

Down-regulated miR-28-5p in human hepatocellular carcinoma correlated with tumor proliferation and migration by targeting insulin-like growth factor-1 (IGF-1)

“…Insulin-like growth factor 1 (IGF1) is a growth factor controlling cell proliferation, differentiation, and apoptosis. Abnormal expression of IGF1 promoted metastatic activity of tumor cells [24]. IGF1 signaling is a mediator of both PI3K/AKT and ERK/P38 signaling and has been demonstrated to enhance wide variety of tumorigenesis [15,24,25].…”

“…Abnormal expression of IGF1 promoted metastatic activity of tumor cells [24]. IGF1 signaling is a mediator of both PI3K/AKT and ERK/P38 signaling and has been demonstrated to enhance wide variety of tumorigenesis [15,24,25]. The emerging importance of miRNAs in the regulation of proteins associated with proliferation, survival, and PI3K/AKT pathway underscores the importance of uncovering mechanisms governing the expression of these small RNAs as a means to better understand the complicated processes of tumorigenesis and cancer cell progression [26,27].…”

Metformin decreases IGF1-induced cell proliferation and protein synthesis through AMP-activated protein kinase in cultured bovine granulosa cells

“…Thus, metformin-induced AMPK activation could inhibit the expression of cyclins D2 and E expression and consequently cell proliferation in response to IGF1 in bovine granulosa cells. AKT and MAPK3/1 are the main signaling pathways that control the growth of the granulosa cells in response to IGF1 (Hu et al 2004, Goto et al 2009). In our study, metformin did not affect IGF1-induced AKT phosphorylation (data not shown).…”

“…After activation, MAPK3/1 phosphorylates several downstream elements, including Elk-1 or P90RSK. In granulosa cells, activation of the PI3K or the MAPK pathway by IGF1 has been reported to stimulate proliferation, differentiation, and/or cell survival (Hu et al 2004, Tosca et al 2005, Goto et al 2009). Metformin treatment decreases cell proliferation of various cells including breast cancer cells and endometriotic stromal cells (Takemura et al 2007, Alimova et al 2009).…”

PI3K/PTEN/Akt and TSC/mTOR signaling pathways, ovarian dysfunction, and infertility: an update

“…Dephosphorylation of Akt with PTEN induced by LH/hCG abolished cell proliferation stimulated with IGF1 in luteinizing GCs. The results indicated that PTEN is a trigger for the proliferation/differentiation transition in human GCs (Goto et al 2009). Fan et al (2008 selectively disrupted Pten expression in GCs and mated Pten-deficient mice with transgenic mice expressing cAMP response element recombinase driven by the Cyp19 promoter.…”