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Overexpression of 17β-hydroxysteroid dehydrogenase type 10 increases pheochromocytoma cell growth and resistance to cell death.

Carlson EA, Marquez RT, Du F, Wang Y, Xu L, Yan SS - BMC Cancer (2015)

Bottom Line: Across disease states, increased HSD10 levels can have a profound and varied impact, such as beneficial in Parkinson's disease and harmful in Alzheimer's disease.In this study, we examined the tumor-promoting effect of HSD10 in pheochromocytoma cells.Our findings demonstrate that overexpression of HSD10 accelerates pheochromocytoma cell growth, enhances cell respiration, and increases cellular resistance to cell death induction.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology & Toxicology, University of Kansas, Lawrence, KS, 66047, USA. e086c574@ku.edu.

ABSTRACT

Background: 17β-hydroxysteroid dehydrogenase type 10 (HSD10) has been shown to play a protective role in cells undergoing stress. Upregulation of HSD10 under nutrient-limiting conditions leads to recovery of a homeostatic state. Across disease states, increased HSD10 levels can have a profound and varied impact, such as beneficial in Parkinson's disease and harmful in Alzheimer's disease. Recently, HSD10 overexpression has been observed in some prostate and bone cancers, consistently correlating with poor patient prognosis. As the role of HSD10 in cancer remains underexplored, we propose that cancer cells utilize this enzyme to promote cancer cell survival under cell death conditions.

Methods: The proliferative effect of HSD10 was examined in transfected pheochromocytoma cells by growth curve analysis and a xenograft model. Fluctuations in mitochondrial bioenergetics were evaluated by electron transport chain complex enzyme activity assays and energy production. Additionally, the effect of HSD10 on pheochromocytoma resistance to cell death was investigated using TUNEL staining, MTT, and complex IV enzyme activity assays.

Results: In this study, we examined the tumor-promoting effect of HSD10 in pheochromocytoma cells. Overexpression of HSD10 increased pheochromocytoma cell growth in both in vitro cell culture and an in vivo xenograft mouse model. The increases in respiratory enzymes and energy generation observed in HSD10-overexpressing cells likely supported the accelerated growth rate observed. Furthermore, cells overexpressing HSD10 were more resistant to oxidative stress-induced perturbation.

Conclusions: Our findings demonstrate that overexpression of HSD10 accelerates pheochromocytoma cell growth, enhances cell respiration, and increases cellular resistance to cell death induction. This suggests that blockade of HSD10 may halt and/or prevent cancer growth, thus providing a promising novel target for cancer patients as a screening or therapeutic option.

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Related in: MedlinePlus

Effect of HSD10-modification onin vitrocell growth andin vivotumor growth. A. Growth curve depicting the number of EV and HSD10 ov cells measured over seven days demonstrated that HSD10 ov cells grew faster in cell culture. Results displayed as cells × 104 per ml (n = 9). B. Growth curve displaying the number of control shRNA and HSD10 shRNA cells measured over seven days showed that HSD10 shRNA cells grew slower than control shRNA cells. Results depicted as cells × 104 per ml (n = 9). C. EV and HSD10 ov cells were injected into the mammary fat pad tissue of 20 two-month old female SCID mice. Day 30 tumor growth in two SCID mice inoculated with EV (left mouse) or HSD10 ov (right mouse) cells demonstrated considerable tumor growth in the HSD10 tumor mouse when observed beside the EV tumor mouse. Visualization of tumors was performed 24 hours post-injection of 15 nmol 2-DG optical dye with an In-Vivo Multispectral FX PRO imager. Arrows point to tumors. D. Quantification of tumor growth in all SCID mice injected with EV (n = 8) or HSD10 ov (n = 12) cells grown over a total of 32 days, depicted in tumor volume (mm3). Data presented as mean ± SE. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus control group.
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Fig4: Effect of HSD10-modification onin vitrocell growth andin vivotumor growth. A. Growth curve depicting the number of EV and HSD10 ov cells measured over seven days demonstrated that HSD10 ov cells grew faster in cell culture. Results displayed as cells × 104 per ml (n = 9). B. Growth curve displaying the number of control shRNA and HSD10 shRNA cells measured over seven days showed that HSD10 shRNA cells grew slower than control shRNA cells. Results depicted as cells × 104 per ml (n = 9). C. EV and HSD10 ov cells were injected into the mammary fat pad tissue of 20 two-month old female SCID mice. Day 30 tumor growth in two SCID mice inoculated with EV (left mouse) or HSD10 ov (right mouse) cells demonstrated considerable tumor growth in the HSD10 tumor mouse when observed beside the EV tumor mouse. Visualization of tumors was performed 24 hours post-injection of 15 nmol 2-DG optical dye with an In-Vivo Multispectral FX PRO imager. Arrows point to tumors. D. Quantification of tumor growth in all SCID mice injected with EV (n = 8) or HSD10 ov (n = 12) cells grown over a total of 32 days, depicted in tumor volume (mm3). Data presented as mean ± SE. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus control group.

Mentions: After evaluating the effect of HSD10 on mitochondrial processes, we determined the effect of HSD10 overexpression on cancer cell growth. Using in vitro cell culture, we performed growth rate curves using both PC-12 HSD10 overexpression and PC-12 HSD10 knockdown cell lines. As shown in Figure 4A, HSD10 ov cells grew at a significantly faster rate compared to EV cells over seven days. Knockdown of HSD10 led to a considerable decrease in growth rate compared with control shRNA cells (Figure 4B). Taken together, these results suggest that HSD10 promotes pheochromocytoma cell growth in cell culture and that knockdown of HSD10 has a reverse effect on cancer cell growth.Figure 4


Overexpression of 17β-hydroxysteroid dehydrogenase type 10 increases pheochromocytoma cell growth and resistance to cell death.

Carlson EA, Marquez RT, Du F, Wang Y, Xu L, Yan SS - BMC Cancer (2015)

Effect of HSD10-modification onin vitrocell growth andin vivotumor growth. A. Growth curve depicting the number of EV and HSD10 ov cells measured over seven days demonstrated that HSD10 ov cells grew faster in cell culture. Results displayed as cells × 104 per ml (n = 9). B. Growth curve displaying the number of control shRNA and HSD10 shRNA cells measured over seven days showed that HSD10 shRNA cells grew slower than control shRNA cells. Results depicted as cells × 104 per ml (n = 9). C. EV and HSD10 ov cells were injected into the mammary fat pad tissue of 20 two-month old female SCID mice. Day 30 tumor growth in two SCID mice inoculated with EV (left mouse) or HSD10 ov (right mouse) cells demonstrated considerable tumor growth in the HSD10 tumor mouse when observed beside the EV tumor mouse. Visualization of tumors was performed 24 hours post-injection of 15 nmol 2-DG optical dye with an In-Vivo Multispectral FX PRO imager. Arrows point to tumors. D. Quantification of tumor growth in all SCID mice injected with EV (n = 8) or HSD10 ov (n = 12) cells grown over a total of 32 days, depicted in tumor volume (mm3). Data presented as mean ± SE. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus control group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384325&req=5

Fig4: Effect of HSD10-modification onin vitrocell growth andin vivotumor growth. A. Growth curve depicting the number of EV and HSD10 ov cells measured over seven days demonstrated that HSD10 ov cells grew faster in cell culture. Results displayed as cells × 104 per ml (n = 9). B. Growth curve displaying the number of control shRNA and HSD10 shRNA cells measured over seven days showed that HSD10 shRNA cells grew slower than control shRNA cells. Results depicted as cells × 104 per ml (n = 9). C. EV and HSD10 ov cells were injected into the mammary fat pad tissue of 20 two-month old female SCID mice. Day 30 tumor growth in two SCID mice inoculated with EV (left mouse) or HSD10 ov (right mouse) cells demonstrated considerable tumor growth in the HSD10 tumor mouse when observed beside the EV tumor mouse. Visualization of tumors was performed 24 hours post-injection of 15 nmol 2-DG optical dye with an In-Vivo Multispectral FX PRO imager. Arrows point to tumors. D. Quantification of tumor growth in all SCID mice injected with EV (n = 8) or HSD10 ov (n = 12) cells grown over a total of 32 days, depicted in tumor volume (mm3). Data presented as mean ± SE. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus control group.
Mentions: After evaluating the effect of HSD10 on mitochondrial processes, we determined the effect of HSD10 overexpression on cancer cell growth. Using in vitro cell culture, we performed growth rate curves using both PC-12 HSD10 overexpression and PC-12 HSD10 knockdown cell lines. As shown in Figure 4A, HSD10 ov cells grew at a significantly faster rate compared to EV cells over seven days. Knockdown of HSD10 led to a considerable decrease in growth rate compared with control shRNA cells (Figure 4B). Taken together, these results suggest that HSD10 promotes pheochromocytoma cell growth in cell culture and that knockdown of HSD10 has a reverse effect on cancer cell growth.Figure 4

Bottom Line: Across disease states, increased HSD10 levels can have a profound and varied impact, such as beneficial in Parkinson's disease and harmful in Alzheimer's disease.In this study, we examined the tumor-promoting effect of HSD10 in pheochromocytoma cells.Our findings demonstrate that overexpression of HSD10 accelerates pheochromocytoma cell growth, enhances cell respiration, and increases cellular resistance to cell death induction.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology & Toxicology, University of Kansas, Lawrence, KS, 66047, USA. e086c574@ku.edu.

ABSTRACT

Background: 17β-hydroxysteroid dehydrogenase type 10 (HSD10) has been shown to play a protective role in cells undergoing stress. Upregulation of HSD10 under nutrient-limiting conditions leads to recovery of a homeostatic state. Across disease states, increased HSD10 levels can have a profound and varied impact, such as beneficial in Parkinson's disease and harmful in Alzheimer's disease. Recently, HSD10 overexpression has been observed in some prostate and bone cancers, consistently correlating with poor patient prognosis. As the role of HSD10 in cancer remains underexplored, we propose that cancer cells utilize this enzyme to promote cancer cell survival under cell death conditions.

Methods: The proliferative effect of HSD10 was examined in transfected pheochromocytoma cells by growth curve analysis and a xenograft model. Fluctuations in mitochondrial bioenergetics were evaluated by electron transport chain complex enzyme activity assays and energy production. Additionally, the effect of HSD10 on pheochromocytoma resistance to cell death was investigated using TUNEL staining, MTT, and complex IV enzyme activity assays.

Results: In this study, we examined the tumor-promoting effect of HSD10 in pheochromocytoma cells. Overexpression of HSD10 increased pheochromocytoma cell growth in both in vitro cell culture and an in vivo xenograft mouse model. The increases in respiratory enzymes and energy generation observed in HSD10-overexpressing cells likely supported the accelerated growth rate observed. Furthermore, cells overexpressing HSD10 were more resistant to oxidative stress-induced perturbation.

Conclusions: Our findings demonstrate that overexpression of HSD10 accelerates pheochromocytoma cell growth, enhances cell respiration, and increases cellular resistance to cell death induction. This suggests that blockade of HSD10 may halt and/or prevent cancer growth, thus providing a promising novel target for cancer patients as a screening or therapeutic option.

Show MeSH
Related in: MedlinePlus