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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

Effect of PRL and AG490 on bcl-xl, bcl-2, survivin and Mcl-1 induction in cervical cancer cells. HeLa, SiHa and C-33 A were treated with either PRL alone or in combination with AG490 inhibitor. a Induction of pS727-STAT3. b Induction of antiapoptotic genes bcl-xl, bcl-2, survivin and Mcl-1.c Apoptosis in HeLa cells after stimuli with Etoposide, PRL and AG490
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Fig4: Effect of PRL and AG490 on bcl-xl, bcl-2, survivin and Mcl-1 induction in cervical cancer cells. HeLa, SiHa and C-33 A were treated with either PRL alone or in combination with AG490 inhibitor. a Induction of pS727-STAT3. b Induction of antiapoptotic genes bcl-xl, bcl-2, survivin and Mcl-1.c Apoptosis in HeLa cells after stimuli with Etoposide, PRL and AG490

Mentions: STAT3 induction in cervical cancer cell lines was the only pathway that showed activation after PRL stimulus compared to HaCaT. Therefore, to test the functional relevance of active STAT3 in the induction of antiapoptotic genes, we inhibited the JAK/STAT pathway by using AG490 inhibitor. In order to evaluate effectively that the signaling pathway had been inhibited, the induction of pS727-STAT3 was assessed. The results showed that the increment in the PRL-mediated phosphorylation of STAT3 in the cell lines HeLa, SiHa and C-33 A was detectable 48 h after treatment and that co-stimulation with the AG490 reduced this effect in the three cervical cancer cell lines (Fig. 4a).Fig. 3


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)

Effect of PRL and AG490 on bcl-xl, bcl-2, survivin and Mcl-1 induction in cervical cancer cells. HeLa, SiHa and C-33 A were treated with either PRL alone or in combination with AG490 inhibitor. a Induction of pS727-STAT3. b Induction of antiapoptotic genes bcl-xl, bcl-2, survivin and Mcl-1.c Apoptosis in HeLa cells after stimuli with Etoposide, PRL and AG490
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Effect of PRL and AG490 on bcl-xl, bcl-2, survivin and Mcl-1 induction in cervical cancer cells. HeLa, SiHa and C-33 A were treated with either PRL alone or in combination with AG490 inhibitor. a Induction of pS727-STAT3. b Induction of antiapoptotic genes bcl-xl, bcl-2, survivin and Mcl-1.c Apoptosis in HeLa cells after stimuli with Etoposide, PRL and AG490
Mentions: STAT3 induction in cervical cancer cell lines was the only pathway that showed activation after PRL stimulus compared to HaCaT. Therefore, to test the functional relevance of active STAT3 in the induction of antiapoptotic genes, we inhibited the JAK/STAT pathway by using AG490 inhibitor. In order to evaluate effectively that the signaling pathway had been inhibited, the induction of pS727-STAT3 was assessed. The results showed that the increment in the PRL-mediated phosphorylation of STAT3 in the cell lines HeLa, SiHa and C-33 A was detectable 48 h after treatment and that co-stimulation with the AG490 reduced this effect in the three cervical cancer cell lines (Fig. 4a).Fig. 3

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