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Interferon-α enhances the susceptibility of renal cell carcinoma to rapamycin by suppressing mTOR activity.

Han X, Shang D, Han T, Xu X, Tian Y - Exp Ther Med (2014)

Bottom Line: The observations indicated that IFN-α significantly increased the susceptibility of RCC cells to RPM and the synergistic effect of IFN-α and RPM against RCC cells was confirmed in all three RCC cell lines.The mTOR pathway was shown to be associated with the synergistic effect of IFN-α and RPM against RCC.Therefore, the results of the present study indicate that the mTOR pathway plays an important role in the synergistic effect of IFN-α and RPM against RCC cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China.

ABSTRACT
The aim of the present study was to investigate the antiproliferative effects of interferon (IFN)-α and rapamycin (RPM) on renal cell carcinoma (RCC) cells and examine the synergistic growth suppression conferred by IFN-α and RPM. The effects of IFN-α and/or RPM on RCC cells were determined using a WST-1 assay and the synergy of IFN-α and RPM against three RCC cell lines was analyzed with isobolographic analysis. The expression of mammalian target of rapamycin (mTOR) was downregulated by RNAi, and the expression and phosphorylation of proteins in the mTOR pathway following treatment with IFN-α and/or RPM was examined by western blot analysis. The observations indicated that IFN-α significantly increased the susceptibility of RCC cells to RPM and the synergistic effect of IFN-α and RPM against RCC cells was confirmed in all three RCC cell lines. The mTOR pathway was shown to be associated with the synergistic effect of IFN-α and RPM against RCC. IFN-α and RPM alone decreased the phosphorylation of mTOR, p70 S6 kinase, S6 and 4E binding protein 1, and IFN-α significantly enhanced the RPM-induced suppression of the mTOR pathway. However, in RCC cells with low mTOR activity, the synergy of IFN-α and RPM was eliminated. Therefore, the results of the present study indicate that the mTOR pathway plays an important role in the synergistic effect of IFN-α and RPM against RCC cells. Thus, mTOR may serve as an effective therapeutic target in the treatment of advanced RCC.

No MeSH data available.


Related in: MedlinePlus

Effect of mTOR activity on the synergy of IFN-α and RPM. (A) Western blot analysis showing the expression of mTOR in two RCC cell lines transfected with RNAi. Bar graphs demonstrating the combination effect of IFN-α and RPM on m-TOR silenced (B) ACHN and (C) A498 RCC cells. (D) Effect of IFN-α and RPM on two m-TOR silenced RCC cell lines based on isobolographic analysis. All determinations were performed in triplicate and error bars represent SD. *P<0.01 vs. RPM alone. mTOR; mammalian target of rapamycin; IFN, interferon; RPM, rapamycin; RCC, renal cell carcinoma.
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f3-etm-08-01-0267: Effect of mTOR activity on the synergy of IFN-α and RPM. (A) Western blot analysis showing the expression of mTOR in two RCC cell lines transfected with RNAi. Bar graphs demonstrating the combination effect of IFN-α and RPM on m-TOR silenced (B) ACHN and (C) A498 RCC cells. (D) Effect of IFN-α and RPM on two m-TOR silenced RCC cell lines based on isobolographic analysis. All determinations were performed in triplicate and error bars represent SD. *P<0.01 vs. RPM alone. mTOR; mammalian target of rapamycin; IFN, interferon; RPM, rapamycin; RCC, renal cell carcinoma.

Mentions: The effect of mTOR activity on the synergy of IFN-α and RPM against RCC was investigated. The expression of mTOR was downregulated by RNAi and the results indicated that mTOR expression was suppressed effectively in ACHN and A498 cells (Fig. 3A). Regardless of mTOR expression, IFN-α enhanced the susceptibility of RCC to RPM in ACHN and A498 cells (Fig. 3B and C). However, the synergy of the two agents was eliminated in these cell lines, as an additive effect was indicated by isobolographic analysis (Fig. 3D). These results indicate that mTOR activity is necessary for the synergistic effect of IFN-α and RPM against RCC cells.


Interferon-α enhances the susceptibility of renal cell carcinoma to rapamycin by suppressing mTOR activity.

Han X, Shang D, Han T, Xu X, Tian Y - Exp Ther Med (2014)

Effect of mTOR activity on the synergy of IFN-α and RPM. (A) Western blot analysis showing the expression of mTOR in two RCC cell lines transfected with RNAi. Bar graphs demonstrating the combination effect of IFN-α and RPM on m-TOR silenced (B) ACHN and (C) A498 RCC cells. (D) Effect of IFN-α and RPM on two m-TOR silenced RCC cell lines based on isobolographic analysis. All determinations were performed in triplicate and error bars represent SD. *P<0.01 vs. RPM alone. mTOR; mammalian target of rapamycin; IFN, interferon; RPM, rapamycin; RCC, renal cell carcinoma.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061221&req=5

f3-etm-08-01-0267: Effect of mTOR activity on the synergy of IFN-α and RPM. (A) Western blot analysis showing the expression of mTOR in two RCC cell lines transfected with RNAi. Bar graphs demonstrating the combination effect of IFN-α and RPM on m-TOR silenced (B) ACHN and (C) A498 RCC cells. (D) Effect of IFN-α and RPM on two m-TOR silenced RCC cell lines based on isobolographic analysis. All determinations were performed in triplicate and error bars represent SD. *P<0.01 vs. RPM alone. mTOR; mammalian target of rapamycin; IFN, interferon; RPM, rapamycin; RCC, renal cell carcinoma.
Mentions: The effect of mTOR activity on the synergy of IFN-α and RPM against RCC was investigated. The expression of mTOR was downregulated by RNAi and the results indicated that mTOR expression was suppressed effectively in ACHN and A498 cells (Fig. 3A). Regardless of mTOR expression, IFN-α enhanced the susceptibility of RCC to RPM in ACHN and A498 cells (Fig. 3B and C). However, the synergy of the two agents was eliminated in these cell lines, as an additive effect was indicated by isobolographic analysis (Fig. 3D). These results indicate that mTOR activity is necessary for the synergistic effect of IFN-α and RPM against RCC cells.

Bottom Line: The observations indicated that IFN-α significantly increased the susceptibility of RCC cells to RPM and the synergistic effect of IFN-α and RPM against RCC cells was confirmed in all three RCC cell lines.The mTOR pathway was shown to be associated with the synergistic effect of IFN-α and RPM against RCC.Therefore, the results of the present study indicate that the mTOR pathway plays an important role in the synergistic effect of IFN-α and RPM against RCC cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China.

ABSTRACT
The aim of the present study was to investigate the antiproliferative effects of interferon (IFN)-α and rapamycin (RPM) on renal cell carcinoma (RCC) cells and examine the synergistic growth suppression conferred by IFN-α and RPM. The effects of IFN-α and/or RPM on RCC cells were determined using a WST-1 assay and the synergy of IFN-α and RPM against three RCC cell lines was analyzed with isobolographic analysis. The expression of mammalian target of rapamycin (mTOR) was downregulated by RNAi, and the expression and phosphorylation of proteins in the mTOR pathway following treatment with IFN-α and/or RPM was examined by western blot analysis. The observations indicated that IFN-α significantly increased the susceptibility of RCC cells to RPM and the synergistic effect of IFN-α and RPM against RCC cells was confirmed in all three RCC cell lines. The mTOR pathway was shown to be associated with the synergistic effect of IFN-α and RPM against RCC. IFN-α and RPM alone decreased the phosphorylation of mTOR, p70 S6 kinase, S6 and 4E binding protein 1, and IFN-α significantly enhanced the RPM-induced suppression of the mTOR pathway. However, in RCC cells with low mTOR activity, the synergy of IFN-α and RPM was eliminated. Therefore, the results of the present study indicate that the mTOR pathway plays an important role in the synergistic effect of IFN-α and RPM against RCC cells. Thus, mTOR may serve as an effective therapeutic target in the treatment of advanced RCC.

No MeSH data available.


Related in: MedlinePlus