Follicle-Stimulating Hormone Activates Mitogen-Activated Protein Kinase in Preneoplastic and Neoplastic Ovarian Surface Epithelial Cells

Abstract

To investigate the role of FSH in ovarian cancer development, the present study examined the expression of FSH receptor (FSH-R) and the effect of FSH on proliferation of normal, preneoplastic, and neoplastic ovarian surface epithelium (OSE) cells. Recently, immortalized OSE (IOSE) cell lines, including IOSE-29 (preneoplastic) and IOSE-29EC (neoplastic), were used. Our results indicated that FSH-R mRNA was expressed and that FSH exerted a growth stimulatory effect in normal, preneoplastic, and neoplastic OSE cells. To investigate the mechanism of the growth stimulatory effect, the activation of MAPKs by FSH was examined in preneoplastic and neoplastic OSE cells. Treatment with FSH resulted in MAPK activation of IOSE-29 and IOSE-29EC cells, whereas the stimulatory effect of FSH on cellular proliferation and MAPK activation was completely abolished in the presence of PD98059, a MAPK kinase inhibitor, suggesting that the growth stimulatory effect of FSH is mediated through MAPK activation in these OSE cells. In a time-dependent study, FSH significantly increased MAPK activity at 5-10 min in IOSE-29 cells. The activated MAPK declined to the control level after 20 min in these cells. Similarly, treatment with FSH significantly induced MAPK activation after 5 min and sustained it for 60 min in IOSE-29EC cells. In addition, treatment with FSH resulted in substantial phosphorylation of Elk-1, confirming that FSH action is mediated via activation of MAPK. In conclusion, we have demonstrated that FSH-R was expressed, and FSH induced growth stimulation in normal, preneoplastic, and neoplastic OSE cells. Furthermore, treatment with FSH stimulated activation of the MAPK cascade and phosphorylated Elk-1 in neoplastic OSE cells. These results suggest that the MAPK cascade may be involved in cellular functions such as growth stimulation in response to FSH in preneoplastic and neoplastic OSE cells.

Follicle stimulating hormone‐induced growth promotion and gene expression profiles on ovarian surface epithelial cells

“…Similar to the previous reports, 3,7,14,15 we showed a significant increase in cell proliferation by FSH treatment on human OSE cell lines, all proven to express FSHR, in dose-and time-dependent manner. Several mechanisms were discussed by other investigators for the FSH stimulated cell proliferation, such as mitogen-activated protein kinase (MAPK) cascade 15 and extracellular-regulated kinase (ERK1 and ERK2) cascade.…”

“…Several mechanisms were discussed by other investigators for the FSH stimulated cell proliferation, such as mitogen-activated protein kinase (MAPK) cascade 15 and extracellular-regulated kinase (ERK1 and ERK2) cascade. 14 In our study, we made 2 cell lines, CHO/FSHR 1 and CHO/FSHR 2, by transfecting human FSHR to CHO cell line.…”

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

“…Besides the observed effect on normal ovaries, FSH treatment is also reported to activate epithelial cell proliferation and oncogenesis in several human OSE immortalized normal, neoplastic (IOSE-29, IOSE-29E, and HOSE), and ovarian cancer cell lines (OVCAR-3 and OVCA) (Schiffenbauer et al 1997, Zheng et al 2000, Syed et al 2001, Choi et al 2004, Ji et al 2004, Abd-Elaziz et al 2005. Interestingly, this effect of FSH is associated with activation of MAPK/ERK rather than via the cAMP pathway (Choi et al 2002(Choi et al , 2005. Li et al (2007) showed that FSH acts on tumorigenic mouse ovary surface epithelium cell line ID8 via the growth factor-type receptor isoform (FSHR3) to bring about proliferation via calcium signaling and the ERK pathway -distinct from the canonical cAMP pathway associated with G protein-coupled FSHR1 isoform.…”

Origin of carcinoma associated fibroblasts

“…[115][116][117][118] The fibroblast response is hardwired in the genome as part of the cancer's resemblance to a chronic wound, aiming at support of epithelial cell survival and expansion. [119][120][121][122][123][124][125][126][127][128] In addition to parsimony, this hypothesis offers clear predictions to scientifically test against corresponding null hypotheses; (1) That co-culture of cancer cells with normal fibroblasts will induce expression of CAF-specific genes in the fibroblasts, [63][64][65][66][67][68][69][70][71] [63][64][65][66][67][68][69][70][71] Many of the genes shown to be activated in these co-cultures are known markers of CAFs in vivo, such as MMP1, MMP3, collagens, TNC, etc. Evidence that this reciprocal interaction promotes cancer includes the anti-cancer effect of Imatinib, on carcinoma animal models.…”