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Methylseleninic acid elevates REDD1 and inhibits prostate cancer cell growth despite AKT activation and mTOR dysregulation in hypoxia.

Sinha I, Allen JE, Pinto JT, Sinha R - Cancer Med (2014)

Bottom Line: We have now extended these studies to evaluate the impact of MSeA on REDD1 (an mTOR inhibitor) in inducing cell death of invasive prostate cancer cells in hypoxia.Furthermore, REDD1 induction by MSeA is independent of AKT and the mTOR inhibition in prostate cancer cells causes partial resistance to MSeA-induced growth reduction in hypoxia.Our data suggest that MSeA induces REDD1 and inhibits prostate cancer cell growth in hypoxia despite activation of AKT and dysregulation of mTOR.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Penn State Hershey Cancer Institute, Hershey, Pennsylvania.

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PC-3M-Luc tumor growth inhibition in MSeA-treated nude mice. PC-3M-Luc cells were injected s.c. into nude mice and treated with increasing doses of MSeA (i.p.) as described in materials and methods. (A) Tumor volume is reduced by MSeA treatment at the end of study (P < 0.05). Number of Ki67-positive cells was also reduced in tumor sections following MSeA treatment (inset). (B) Tumor burden as measured by change in luciferase activity from baseline is reduced following MSeA treatment (P < 0.05). (C) BLI measurements from representative saline and MSeA-treated PC-3M-Luc-bearing tumors and their respective characteristics. (D) Body weights of MSeA-treated nude mice are reduced compared to saline-treated control mice but the changes are not statistically significant. MSeA, methylseleninic acid; BLI, bioluminescence imaging.
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fig05: PC-3M-Luc tumor growth inhibition in MSeA-treated nude mice. PC-3M-Luc cells were injected s.c. into nude mice and treated with increasing doses of MSeA (i.p.) as described in materials and methods. (A) Tumor volume is reduced by MSeA treatment at the end of study (P < 0.05). Number of Ki67-positive cells was also reduced in tumor sections following MSeA treatment (inset). (B) Tumor burden as measured by change in luciferase activity from baseline is reduced following MSeA treatment (P < 0.05). (C) BLI measurements from representative saline and MSeA-treated PC-3M-Luc-bearing tumors and their respective characteristics. (D) Body weights of MSeA-treated nude mice are reduced compared to saline-treated control mice but the changes are not statistically significant. MSeA, methylseleninic acid; BLI, bioluminescence imaging.

Mentions: Although, PC3 cells have been used for xenograft model for testing MSeA by oral route for about 49 days 43, our intent was to investigate the efficacy of MSeA against a highly invasive prostate cancer cell line (PC-3M). Therefore, we decided an i.p. route of treatment for a shorter duration. The PC-3M-Luc cells were injected subcutaneously into left flanks of nude mice. Tumor volumes showed a steady growth in control while the MSeA-treated tumors exhibited reduced volumes (P < 0.05) at the end of the experiment (Fig. 5A). Similarly, number of Ki67-positive cells was decreased in the tumors following MSeA treatment (control: 123.5 ± 2.6; MSeA: 62.7 ± 18.4, P < 0.05). Furthermore, tumor burdens in control and MSeA-treated mice were reflected by change (P < 0.05) in total luminescence flux by day 20 post-treatment (Fig. 5B). The BLI of representative mice from control and MSeA-treated groups are shown in Figure 5C. Body weights did not change significantly between control and treated groups during the short-term treatment with MSeA (Fig. 5D). At the end of the experiment, tumor weights were 0.91 ± 0.54 g in control and 0.44 ± 0.23 g in MSeA-treated mice. Despite the apparent changes in the mean values, differences in overall tumor weights were not statistically significant due to large variation between groups. These findings differ slightly from Li et al. 43 who showed that inhibition of tumor growth occurred after oral MSeA treatment for longer duration in xenograft models using LNCaP, DU145, and PC3 cells.


Methylseleninic acid elevates REDD1 and inhibits prostate cancer cell growth despite AKT activation and mTOR dysregulation in hypoxia.

Sinha I, Allen JE, Pinto JT, Sinha R - Cancer Med (2014)

PC-3M-Luc tumor growth inhibition in MSeA-treated nude mice. PC-3M-Luc cells were injected s.c. into nude mice and treated with increasing doses of MSeA (i.p.) as described in materials and methods. (A) Tumor volume is reduced by MSeA treatment at the end of study (P < 0.05). Number of Ki67-positive cells was also reduced in tumor sections following MSeA treatment (inset). (B) Tumor burden as measured by change in luciferase activity from baseline is reduced following MSeA treatment (P < 0.05). (C) BLI measurements from representative saline and MSeA-treated PC-3M-Luc-bearing tumors and their respective characteristics. (D) Body weights of MSeA-treated nude mice are reduced compared to saline-treated control mice but the changes are not statistically significant. MSeA, methylseleninic acid; BLI, bioluminescence imaging.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig05: PC-3M-Luc tumor growth inhibition in MSeA-treated nude mice. PC-3M-Luc cells were injected s.c. into nude mice and treated with increasing doses of MSeA (i.p.) as described in materials and methods. (A) Tumor volume is reduced by MSeA treatment at the end of study (P < 0.05). Number of Ki67-positive cells was also reduced in tumor sections following MSeA treatment (inset). (B) Tumor burden as measured by change in luciferase activity from baseline is reduced following MSeA treatment (P < 0.05). (C) BLI measurements from representative saline and MSeA-treated PC-3M-Luc-bearing tumors and their respective characteristics. (D) Body weights of MSeA-treated nude mice are reduced compared to saline-treated control mice but the changes are not statistically significant. MSeA, methylseleninic acid; BLI, bioluminescence imaging.
Mentions: Although, PC3 cells have been used for xenograft model for testing MSeA by oral route for about 49 days 43, our intent was to investigate the efficacy of MSeA against a highly invasive prostate cancer cell line (PC-3M). Therefore, we decided an i.p. route of treatment for a shorter duration. The PC-3M-Luc cells were injected subcutaneously into left flanks of nude mice. Tumor volumes showed a steady growth in control while the MSeA-treated tumors exhibited reduced volumes (P < 0.05) at the end of the experiment (Fig. 5A). Similarly, number of Ki67-positive cells was decreased in the tumors following MSeA treatment (control: 123.5 ± 2.6; MSeA: 62.7 ± 18.4, P < 0.05). Furthermore, tumor burdens in control and MSeA-treated mice were reflected by change (P < 0.05) in total luminescence flux by day 20 post-treatment (Fig. 5B). The BLI of representative mice from control and MSeA-treated groups are shown in Figure 5C. Body weights did not change significantly between control and treated groups during the short-term treatment with MSeA (Fig. 5D). At the end of the experiment, tumor weights were 0.91 ± 0.54 g in control and 0.44 ± 0.23 g in MSeA-treated mice. Despite the apparent changes in the mean values, differences in overall tumor weights were not statistically significant due to large variation between groups. These findings differ slightly from Li et al. 43 who showed that inhibition of tumor growth occurred after oral MSeA treatment for longer duration in xenograft models using LNCaP, DU145, and PC3 cells.

Bottom Line: We have now extended these studies to evaluate the impact of MSeA on REDD1 (an mTOR inhibitor) in inducing cell death of invasive prostate cancer cells in hypoxia.Furthermore, REDD1 induction by MSeA is independent of AKT and the mTOR inhibition in prostate cancer cells causes partial resistance to MSeA-induced growth reduction in hypoxia.Our data suggest that MSeA induces REDD1 and inhibits prostate cancer cell growth in hypoxia despite activation of AKT and dysregulation of mTOR.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Penn State Hershey Cancer Institute, Hershey, Pennsylvania.

Show MeSH
Related in: MedlinePlus