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STAT3 activation is required for the antiapoptotic effects of prolactin in cervical cancer cells.

Ramírez de Arellano A, Lopez-Pulido EI, Martínez-Neri PA, Estrada Chávez C, González Lucano R, Fafutis-Morris M, Aguilar-Lemarroy A, Muñoz-Valle JF, Pereira-Suárez AL - Cancer Cell Int. (2015)

Bottom Line: JAK/STAT is an important pathway associated with PRL effects.Significant effects were determined by using ANOVA test.No significant differences were found when analyzing MAPK and PI3K signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco Mexico ; Laboratorio de Inmunología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Sierra Mojada # 950, Colonia Independencia, 44340 Guadalajara, Jalisco Mexico.

ABSTRACT

Background: Prolactin (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.

Methods: Cervical 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.

Results: STAT3 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.

Conclusion: Our 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.

No MeSH data available.


Related in: MedlinePlus

Prolactin induces STAT3 phosphorylation in cervical cancer cell lines by western blot. a HeLa, SiHa and C-33 A. Overexpressing PRLR breast cancer cell lines: MCF-7 and T-47D. Non-tumorigenic immortalized keratinocytes: HaCaT. All the cells were treated under three conditions: no stimulus, 30-min stimulus and 60-min stimulus with PRL (200 ng/mL). b Induction of pS727-STAT3 by western blot, comparisons were made versus non-stimulated cells, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001
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Fig1: Prolactin induces STAT3 phosphorylation in cervical cancer cell lines by western blot. a HeLa, SiHa and C-33 A. Overexpressing PRLR breast cancer cell lines: MCF-7 and T-47D. Non-tumorigenic immortalized keratinocytes: HaCaT. All the cells were treated under three conditions: no stimulus, 30-min stimulus and 60-min stimulus with PRL (200 ng/mL). b Induction of pS727-STAT3 by western blot, comparisons were made versus non-stimulated cells, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001

Mentions: The results showed a differential expression pattern of constitutively active pS727-STAT3 among the analyzed cell lines. In comparison to the HPV-negative C-33 A cells, SiHa and HeLa cells demonstrated a higher pS727-STAT3 basal expression. However, treatment with PRL increased pS727-STAT3 induction in HeLa and C-33 A. In MCF-7 and T-47D, increased induction of pS727-STAT3 by the effect of PRL was also observed. In contrast, no differences at 30 min and a decreased pS727-STAT3 expression at 60 min in the HaCaT cell line were observed (Fig. 1).Fig. 1


STAT3 activation is required for the antiapoptotic effects of prolactin in cervical cancer cells.

Ramírez de Arellano A, Lopez-Pulido EI, Martínez-Neri PA, Estrada Chávez C, González Lucano R, Fafutis-Morris M, Aguilar-Lemarroy A, Muñoz-Valle JF, Pereira-Suárez AL - Cancer Cell Int. (2015)

Prolactin induces STAT3 phosphorylation in cervical cancer cell lines by western blot. a HeLa, SiHa and C-33 A. Overexpressing PRLR breast cancer cell lines: MCF-7 and T-47D. Non-tumorigenic immortalized keratinocytes: HaCaT. All the cells were treated under three conditions: no stimulus, 30-min stimulus and 60-min stimulus with PRL (200 ng/mL). b Induction of pS727-STAT3 by western blot, comparisons were made versus non-stimulated cells, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4559880&req=5

Fig1: Prolactin induces STAT3 phosphorylation in cervical cancer cell lines by western blot. a HeLa, SiHa and C-33 A. Overexpressing PRLR breast cancer cell lines: MCF-7 and T-47D. Non-tumorigenic immortalized keratinocytes: HaCaT. All the cells were treated under three conditions: no stimulus, 30-min stimulus and 60-min stimulus with PRL (200 ng/mL). b Induction of pS727-STAT3 by western blot, comparisons were made versus non-stimulated cells, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001
Mentions: The results showed a differential expression pattern of constitutively active pS727-STAT3 among the analyzed cell lines. In comparison to the HPV-negative C-33 A cells, SiHa and HeLa cells demonstrated a higher pS727-STAT3 basal expression. However, treatment with PRL increased pS727-STAT3 induction in HeLa and C-33 A. In MCF-7 and T-47D, increased induction of pS727-STAT3 by the effect of PRL was also observed. In contrast, no differences at 30 min and a decreased pS727-STAT3 expression at 60 min in the HaCaT cell line were observed (Fig. 1).Fig. 1

Bottom Line: JAK/STAT is an important pathway associated with PRL effects.Significant effects were determined by using ANOVA test.No significant differences were found when analyzing MAPK and PI3K signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco Mexico ; Laboratorio de Inmunología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Sierra Mojada # 950, Colonia Independencia, 44340 Guadalajara, Jalisco Mexico.

ABSTRACT

Background: Prolactin (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.

Methods: Cervical 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.

Results: STAT3 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.

Conclusion: Our 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.

No MeSH data available.


Related in: MedlinePlus