Abstract
BackgroundProlactin (PRL) has been implicated in the development of different types of cancer. However, signaling pathways might be activated depending on various forms of prolactin receptor (PRLR). JAK/STAT is an important pathway associated with PRL effects. The activation of JAK/STAT pathway might activate antiapoptotic genes that could importantly lead to progression of tumorigenesis. Recently, we have reported that PRL is associated with cell survival by inhibition of apoptosis and the precise activated signaling pathways for this process are still questioned. The purpose of this study was to evaluate the activation of different signaling pathways in response to PRL as well as to identify the induction of antiapoptotic genes.MethodsCervical cancer cell lines HeLa, SiHa and C-33 A were stimulated with PRL (200 ng/mL) for 30 and 60 min and non stimulated cells were used to measure basal protein expression. Inhibition assays were performed by using Jak2 specific inhibitor AG490, either alone or in combination with PRL for 48 h. Western blot were carried out to evaluate protein induction of the different signaling pathways and antiapoptotic proteins. Significant effects were determined by using ANOVA test.ResultsSTAT3 was significantly activated in cervical cancer lines in comparison with non-tumorigenic keratinocytes HaCaT. No significant differences were found when analyzing MAPK and PI3K signaling pathways. An increase of antiapoptotic genes Bcl-xl, Bcl-2, survivin and Mcl-1 was observed after stimulus with PRL; however, after inhibition with AG490, the induction of antiapoptotic genes was decreased.ConclusionOur data suggests that STAT3 is an important signaling pathway activated by PRL in cervical cancer cells and it modulates the induction of antiapoptotic genes. Blocking STAT3 could represent a possible therapeutic strategy in cervical cancer.
Highlights
Prolactin (PRL) has been implicated in the development of different types of cancer
We reported that PRL and prolactin receptor (PRLR) induction is associated with cell survival, mainly by inhibition of apoptosis, but not by inducing proliferation, in cervical cancer cell lines [15]
To determine the effect of PRL on the activation of different signaling pathways in the uterine cervical cancer cell line compared to non-tumorigenic immortalized keratinocytes HaCaT, all cell lines were stimulated with PRL during 30 and 60 min
Summary
Prolactin (PRL) has been implicated in the development of different types of cancer. signal‐ ing pathways might be activated depending on various forms of prolactin receptor (PRLR). We have reported that PRL is associated with cell survival by inhibition of apoptosis and the precise activated signaling pathways for this process are still questioned. With regard to cervical cancer we reported an overexpression of PRLR and the presence of different forms in tissues derived from cervical cancer in comparison with premalignant lesions and healthy tissues [12] This accumulation in the cytoplasm could be due to alterations in PRLR leading to a decrease of PRLR phosphorylation and subsequent lack of ubiquitination which is associated with the non-degradative process and as a result, the accumulation of PRLR [14]. We reported that PRL and PRLR induction is associated with cell survival, mainly by inhibition of apoptosis, but not by inducing proliferation, in cervical cancer cell lines [15]
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