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Contrasting effect of recombinant human erythropoietin on breast cancer cell response to cisplatin induced cytotoxicity.

Trost N, Juvan P, Sersa G, Debeljak N - Radiol Oncol (2012)

Bottom Line: Gene expression analysis of p53-dependent genes and bcl-2 gene family members confirmed differences between long and short-term rHuEpo effects, indicating the most prominent changes in BCL2 and BAD expression.On the other hand, MDA-MB-231 cells are almost irresponsive to long-term rHuEpo, supposedly due to the mutated p53 and ER(+)/PR(-) status.The p53 and ER/PR status may predict tumour response on rHuEpo and cDDP treatment.

View Article: PubMed Central - PubMed

Affiliation: Center for Functional Genomics and Bio-chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Slovenia.

ABSTRACT

Background: Human recombinant erythropoietin (rHuEpo) that is used for the treatment of the chemotherapy-induced anaemia in cancer patients was shown to cause detrimental effects on the course of disease due to increased adverse events inflicting patient's survival, potentially related to rHuEpo-induced cancer progression. In this study, we elucidate the effect of rHuEpo administration on breast cancer cell proliferation and gene expression after cisplatin (cDDP) induced cytotoxicity.

Materials and methods: Two breast carcinoma models, MCF-7 and MDA-MB-231 cell lines, were used differing in oestrogen (ER) and progesterone (PR) receptors and p53 status. Cells were cultured with or without rHuEpo for 24 h or 9 weeks and their growth characteristics after cDDP treatment were assessed together with expression of genes involved in the p53-signaling pathway.

Results: Short-term exposure of breast cancer cells to rHuEpo lowers their proliferation and reduces cDDP cytotoxic potency. In contrast, long-term exposure of MCF-7 cells to rHuEpo increases proliferation and predisposes MCF-7 cells to cDDP cytotoxicity, but has no effect on MDA-MB-231 cells. MDA-MB-231 cells show altered level of ERK phosphorylation, indicating involvement of MAPK signalling pathway. Gene expression analysis of p53-dependent genes and bcl-2 gene family members confirmed differences between long and short-term rHuEpo effects, indicating the most prominent changes in BCL2 and BAD expression.

Conclusions: Proliferation and survival characteristics of MCF-7 cells are reversely modulated by the length of the rHuEpo exposure. On the other hand, MDA-MB-231 cells are almost irresponsive to long-term rHuEpo, supposedly due to the mutated p53 and ER(+)/PR(-) status. The p53 and ER/PR status may predict tumour response on rHuEpo and cDDP treatment.

No MeSH data available.


Related in: MedlinePlus

Involvement of MAPK (ERK), PI-3K (Akt) and Jak/STAT5 (STAT5) signaling pathways in Epo signaling for MDAMB-231 cell line. (A) Expression of ERK, Akt and STAT5 proteins in short and long-term rHuEpo treated cells. (B) ERK phosphorylation (p-ERK) in short and long-term rHuEpo treated MDA-MB-231cells. p-ERK to ERK ratios after rHuEpo treatment (5, 25 U/mL) were compared with non-treated samples. Table shows densitometry ratios and corresponding standard deviations (SD). (C) ERK phosphorylation (p-ERK) in short-term rHuEpo treated or non-treated cells after the exposure to cDDP. p-ERK to ERK ratios after exposure to cDDP (60, 120 μM/mL) were compared to samples that were not exposed to cDDP. Table shows densitometry ratios and corresponding standard deviations (SD). Asterisk (*) denotes statistical significant differences (p-ERK to ERK ratio) for Type I error α = 0.05. UT7/Epo cells were used as positive controls for Epo signaling.
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f6-rado-46-03-213: Involvement of MAPK (ERK), PI-3K (Akt) and Jak/STAT5 (STAT5) signaling pathways in Epo signaling for MDAMB-231 cell line. (A) Expression of ERK, Akt and STAT5 proteins in short and long-term rHuEpo treated cells. (B) ERK phosphorylation (p-ERK) in short and long-term rHuEpo treated MDA-MB-231cells. p-ERK to ERK ratios after rHuEpo treatment (5, 25 U/mL) were compared with non-treated samples. Table shows densitometry ratios and corresponding standard deviations (SD). (C) ERK phosphorylation (p-ERK) in short-term rHuEpo treated or non-treated cells after the exposure to cDDP. p-ERK to ERK ratios after exposure to cDDP (60, 120 μM/mL) were compared to samples that were not exposed to cDDP. Table shows densitometry ratios and corresponding standard deviations (SD). Asterisk (*) denotes statistical significant differences (p-ERK to ERK ratio) for Type I error α = 0.05. UT7/Epo cells were used as positive controls for Epo signaling.

Mentions: In view of the evidence for the expression and functionality of EpoR in MCF-7 and MDA-MB-231 cells, we evaluated the ability of Epo to signal through well-established pathways that are thought to promote cell proliferation and cytoprotection, specifically the ERK, Akt and STAT5. The analysis of MDA-MB-231 cell line is presented on Figure 6. rHuEpo treatment or exposure to cDDP did not promote phosphorylation of ERK, Akt or STAT5 in MCF-7 cells (data not shown). We also confirmed that STAT5 is not expressed in MCF-7 cells, which was already reported by Yamashita et al.46 and is consistent with qPCR data from our laboratory (data not shown).


Contrasting effect of recombinant human erythropoietin on breast cancer cell response to cisplatin induced cytotoxicity.

Trost N, Juvan P, Sersa G, Debeljak N - Radiol Oncol (2012)

Involvement of MAPK (ERK), PI-3K (Akt) and Jak/STAT5 (STAT5) signaling pathways in Epo signaling for MDAMB-231 cell line. (A) Expression of ERK, Akt and STAT5 proteins in short and long-term rHuEpo treated cells. (B) ERK phosphorylation (p-ERK) in short and long-term rHuEpo treated MDA-MB-231cells. p-ERK to ERK ratios after rHuEpo treatment (5, 25 U/mL) were compared with non-treated samples. Table shows densitometry ratios and corresponding standard deviations (SD). (C) ERK phosphorylation (p-ERK) in short-term rHuEpo treated or non-treated cells after the exposure to cDDP. p-ERK to ERK ratios after exposure to cDDP (60, 120 μM/mL) were compared to samples that were not exposed to cDDP. Table shows densitometry ratios and corresponding standard deviations (SD). Asterisk (*) denotes statistical significant differences (p-ERK to ERK ratio) for Type I error α = 0.05. UT7/Epo cells were used as positive controls for Epo signaling.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472952&req=5

f6-rado-46-03-213: Involvement of MAPK (ERK), PI-3K (Akt) and Jak/STAT5 (STAT5) signaling pathways in Epo signaling for MDAMB-231 cell line. (A) Expression of ERK, Akt and STAT5 proteins in short and long-term rHuEpo treated cells. (B) ERK phosphorylation (p-ERK) in short and long-term rHuEpo treated MDA-MB-231cells. p-ERK to ERK ratios after rHuEpo treatment (5, 25 U/mL) were compared with non-treated samples. Table shows densitometry ratios and corresponding standard deviations (SD). (C) ERK phosphorylation (p-ERK) in short-term rHuEpo treated or non-treated cells after the exposure to cDDP. p-ERK to ERK ratios after exposure to cDDP (60, 120 μM/mL) were compared to samples that were not exposed to cDDP. Table shows densitometry ratios and corresponding standard deviations (SD). Asterisk (*) denotes statistical significant differences (p-ERK to ERK ratio) for Type I error α = 0.05. UT7/Epo cells were used as positive controls for Epo signaling.
Mentions: In view of the evidence for the expression and functionality of EpoR in MCF-7 and MDA-MB-231 cells, we evaluated the ability of Epo to signal through well-established pathways that are thought to promote cell proliferation and cytoprotection, specifically the ERK, Akt and STAT5. The analysis of MDA-MB-231 cell line is presented on Figure 6. rHuEpo treatment or exposure to cDDP did not promote phosphorylation of ERK, Akt or STAT5 in MCF-7 cells (data not shown). We also confirmed that STAT5 is not expressed in MCF-7 cells, which was already reported by Yamashita et al.46 and is consistent with qPCR data from our laboratory (data not shown).

Bottom Line: Gene expression analysis of p53-dependent genes and bcl-2 gene family members confirmed differences between long and short-term rHuEpo effects, indicating the most prominent changes in BCL2 and BAD expression.On the other hand, MDA-MB-231 cells are almost irresponsive to long-term rHuEpo, supposedly due to the mutated p53 and ER(+)/PR(-) status.The p53 and ER/PR status may predict tumour response on rHuEpo and cDDP treatment.

View Article: PubMed Central - PubMed

Affiliation: Center for Functional Genomics and Bio-chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Slovenia.

ABSTRACT

Background: Human recombinant erythropoietin (rHuEpo) that is used for the treatment of the chemotherapy-induced anaemia in cancer patients was shown to cause detrimental effects on the course of disease due to increased adverse events inflicting patient's survival, potentially related to rHuEpo-induced cancer progression. In this study, we elucidate the effect of rHuEpo administration on breast cancer cell proliferation and gene expression after cisplatin (cDDP) induced cytotoxicity.

Materials and methods: Two breast carcinoma models, MCF-7 and MDA-MB-231 cell lines, were used differing in oestrogen (ER) and progesterone (PR) receptors and p53 status. Cells were cultured with or without rHuEpo for 24 h or 9 weeks and their growth characteristics after cDDP treatment were assessed together with expression of genes involved in the p53-signaling pathway.

Results: Short-term exposure of breast cancer cells to rHuEpo lowers their proliferation and reduces cDDP cytotoxic potency. In contrast, long-term exposure of MCF-7 cells to rHuEpo increases proliferation and predisposes MCF-7 cells to cDDP cytotoxicity, but has no effect on MDA-MB-231 cells. MDA-MB-231 cells show altered level of ERK phosphorylation, indicating involvement of MAPK signalling pathway. Gene expression analysis of p53-dependent genes and bcl-2 gene family members confirmed differences between long and short-term rHuEpo effects, indicating the most prominent changes in BCL2 and BAD expression.

Conclusions: Proliferation and survival characteristics of MCF-7 cells are reversely modulated by the length of the rHuEpo exposure. On the other hand, MDA-MB-231 cells are almost irresponsive to long-term rHuEpo, supposedly due to the mutated p53 and ER(+)/PR(-) status. The p53 and ER/PR status may predict tumour response on rHuEpo and cDDP treatment.

No MeSH data available.


Related in: MedlinePlus