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Acquired resistance to zoledronic acid and the parallel acquisition of an aggressive phenotype are mediated by p38-MAP kinase activation in prostate cancer cells.

Milone MR, Pucci B, Bruzzese F, Carbone C, Piro G, Costantini S, Capone F, Leone A, Di Gennaro E, Caraglia M, Budillon A - Cell Death Dis (2013)

Bottom Line: Notably, compared with DU145 parental cells, DU145R80 developed resistance to apoptosis and anoikis, as well as overexpressed the anti-apoptotic protein Bcl-2 and oncoprotein c-Myc.At the molecular level, DU145R80 cells showed strong activation of the p38-MAPK-dependent survival pathway compared with parental sensitive cells.Furthermore, SB203580 treatment reduced the expression of VEGF, Eotaxin-1, IL-12, MMP-9, Bcl-2 and c-Myc.

View Article: PubMed Central - PubMed

Affiliation: Centro di Ricerche Oncologiche di Mercogliano (CROM), Mercogliano (AV), Italy.

ABSTRACT
The nitrogen-containing bisphosphonates (N-BP) zoledronic acid (ZOL) inhibits osteoclast-mediated bone resorption, and it is used to prevent skeletal complications from bone metastases. ZOL has also demonstrated anticancer activities in preclinical models and, recently, in cancer patients, highlighting the interest in determining eventual mechanisms of resistance against this agent. In our study, we selected and characterised a resistant subline of prostate cancer (PCa) cells to better understand the mechanisms, by which tumour cells can escape the antitumour effect of ZOL. DU145R80-resistant cells were selected in about 5 months using stepwise increasing concentrations of ZOL from DU145 parental cells. DU145R80 cells showed a resistance index value of 5.5 and cross-resistance to another N-BP, pamidronate, but not to the non-nitrogen containing BP clodronate. Notably, compared with DU145 parental cells, DU145R80 developed resistance to apoptosis and anoikis, as well as overexpressed the anti-apoptotic protein Bcl-2 and oncoprotein c-Myc. Moreover, DU145R80 cells underwent epithelial to mesenchymal transition (EMT) and showed increased expression of the metalloproteases MMP-2/9, as well as increased invading capability. Interestingly, compared with DU145, DU145R80 cells also increased the gene expression and protein secretion of VEGF and the cytokines Eotaxin-1 and IL-12. At the molecular level, DU145R80 cells showed strong activation of the p38-MAPK-dependent survival pathway compared with parental sensitive cells. Moreover, using the p38-inhibitor SB203580, we completely reversed the resistance to ZOL, as well as EMT marker expression and invasion. Furthermore, SB203580 treatment reduced the expression of VEGF, Eotaxin-1, IL-12, MMP-9, Bcl-2 and c-Myc. Thus, for the first time, we demonstrate that the p38-MAPK pathway can be activated under continuous extensive exposure to ZOL in PCa cells and that the p38-MAPK pathway has a critical role in the induction of resistance, as well as in the acquisition of a more aggressive and invasive phenotype.

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Proposed model for the mechanisms underlying the acquired resistance to ZOL and the parallel acquisition of an aggressive phenotype mediated by p38-MAP Kinase activation
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fig7: Proposed model for the mechanisms underlying the acquired resistance to ZOL and the parallel acquisition of an aggressive phenotype mediated by p38-MAP Kinase activation

Mentions: In conclusion, this study demonstrated, for the first time, that prolonged treatment of PCa cells with ZOL was responsible for the activation of the p38-MAPK, which has a central role in the regulation of several biological process, such as antiapoptotic, prosurvival, proinflammatory and proangiogenic events, as well as EMT activation and invasion (Figure 7). The direct correlation between all the proteins regulating the above events and p38-MAPK was also highlighted by a protein interatomic analysis that was performed using Ingenuity software (Supplementary Figure 2). This protein network could have a critical role to confer ZOL resistance and a more aggressive phenotype to PCa cells. Moreover, this analysis may allow more detailed examination of the molecular mechanisms and could help to plan combination drug treatments aiming to overcome or prevent these occurrences.


Acquired resistance to zoledronic acid and the parallel acquisition of an aggressive phenotype are mediated by p38-MAP kinase activation in prostate cancer cells.

Milone MR, Pucci B, Bruzzese F, Carbone C, Piro G, Costantini S, Capone F, Leone A, Di Gennaro E, Caraglia M, Budillon A - Cell Death Dis (2013)

Proposed model for the mechanisms underlying the acquired resistance to ZOL and the parallel acquisition of an aggressive phenotype mediated by p38-MAP Kinase activation
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3674372&req=5

fig7: Proposed model for the mechanisms underlying the acquired resistance to ZOL and the parallel acquisition of an aggressive phenotype mediated by p38-MAP Kinase activation
Mentions: In conclusion, this study demonstrated, for the first time, that prolonged treatment of PCa cells with ZOL was responsible for the activation of the p38-MAPK, which has a central role in the regulation of several biological process, such as antiapoptotic, prosurvival, proinflammatory and proangiogenic events, as well as EMT activation and invasion (Figure 7). The direct correlation between all the proteins regulating the above events and p38-MAPK was also highlighted by a protein interatomic analysis that was performed using Ingenuity software (Supplementary Figure 2). This protein network could have a critical role to confer ZOL resistance and a more aggressive phenotype to PCa cells. Moreover, this analysis may allow more detailed examination of the molecular mechanisms and could help to plan combination drug treatments aiming to overcome or prevent these occurrences.

Bottom Line: Notably, compared with DU145 parental cells, DU145R80 developed resistance to apoptosis and anoikis, as well as overexpressed the anti-apoptotic protein Bcl-2 and oncoprotein c-Myc.At the molecular level, DU145R80 cells showed strong activation of the p38-MAPK-dependent survival pathway compared with parental sensitive cells.Furthermore, SB203580 treatment reduced the expression of VEGF, Eotaxin-1, IL-12, MMP-9, Bcl-2 and c-Myc.

View Article: PubMed Central - PubMed

Affiliation: Centro di Ricerche Oncologiche di Mercogliano (CROM), Mercogliano (AV), Italy.

ABSTRACT
The nitrogen-containing bisphosphonates (N-BP) zoledronic acid (ZOL) inhibits osteoclast-mediated bone resorption, and it is used to prevent skeletal complications from bone metastases. ZOL has also demonstrated anticancer activities in preclinical models and, recently, in cancer patients, highlighting the interest in determining eventual mechanisms of resistance against this agent. In our study, we selected and characterised a resistant subline of prostate cancer (PCa) cells to better understand the mechanisms, by which tumour cells can escape the antitumour effect of ZOL. DU145R80-resistant cells were selected in about 5 months using stepwise increasing concentrations of ZOL from DU145 parental cells. DU145R80 cells showed a resistance index value of 5.5 and cross-resistance to another N-BP, pamidronate, but not to the non-nitrogen containing BP clodronate. Notably, compared with DU145 parental cells, DU145R80 developed resistance to apoptosis and anoikis, as well as overexpressed the anti-apoptotic protein Bcl-2 and oncoprotein c-Myc. Moreover, DU145R80 cells underwent epithelial to mesenchymal transition (EMT) and showed increased expression of the metalloproteases MMP-2/9, as well as increased invading capability. Interestingly, compared with DU145, DU145R80 cells also increased the gene expression and protein secretion of VEGF and the cytokines Eotaxin-1 and IL-12. At the molecular level, DU145R80 cells showed strong activation of the p38-MAPK-dependent survival pathway compared with parental sensitive cells. Moreover, using the p38-inhibitor SB203580, we completely reversed the resistance to ZOL, as well as EMT marker expression and invasion. Furthermore, SB203580 treatment reduced the expression of VEGF, Eotaxin-1, IL-12, MMP-9, Bcl-2 and c-Myc. Thus, for the first time, we demonstrate that the p38-MAPK pathway can be activated under continuous extensive exposure to ZOL in PCa cells and that the p38-MAPK pathway has a critical role in the induction of resistance, as well as in the acquisition of a more aggressive and invasive phenotype.

Show MeSH
Related in: MedlinePlus