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JQ1 suppresses tumor growth through downregulating LDHA in ovarian cancer.

Qiu H, Jackson AL, Kilgore JE, Zhong Y, Chan LL, Gehrig PA, Zhou C, Bae-Jump VL - Oncotarget (2015)

Bottom Line: JQ1, a selective small-molecule BET bromodomain (BRDs) inhibitor, has been found to suppress tumor progression in several cancer cell types.JQ1 reduced both the activity and phosphorylation of LDHA, inhibited lactate production, and decreased the energy supply to ovarian cancer cell lines and tumors.Taken together, our findings suggest that JQ1 is an efficacious anti-tumor agent in ovarian cancer that is associated with cell cycle arrest, induction of apoptosis and alterations of metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Obsterics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

ABSTRACT
Amplification and overexpression of c-Myc is commonly seen in human ovarian cancers, and this could be a potentially novel therapeutic target for this disease. JQ1, a selective small-molecule BET bromodomain (BRDs) inhibitor, has been found to suppress tumor progression in several cancer cell types. Using ovarian cancer cell lines, a transgenic mouse model, and primary cell cultures from human ovarian cancer tissues, we demonstrated that JQ1 significantly suppressed cellular proliferation and induced cell cycle arrest and apoptosis in ovarian cancer cells and mouse model via targeting c-Myc. In addition, JQ1 had multiple influences on cancer metabolism, particularly in the aerobic glycolysis pathway. JQ1 reduced both the activity and phosphorylation of LDHA, inhibited lactate production, and decreased the energy supply to ovarian cancer cell lines and tumors. Taken together, our findings suggest that JQ1 is an efficacious anti-tumor agent in ovarian cancer that is associated with cell cycle arrest, induction of apoptosis and alterations of metabolism.

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JQ1 suppressed cell growth through the downregulation of LDHA(A) Alterations in LDHA protein after transfection with siRNA targeting LDHA (si-LDHA) for 48 hours. (B) The impact of JQ1 on cell growth after treatment of si-LDHA. (C) The effects of JQ1 on cellular apoptosis after treatment with si-LDHA (24 hours). (D) The effects of JQ1 on G1 cell cycle arrest after treatment with si-LDHA (24 hours). (E and F) The effects of JQ1 on ATP and lactate production after treatment with si-LDHA (24 hours) (*p < 0.05; **p < 0.01).
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Figure 6: JQ1 suppressed cell growth through the downregulation of LDHA(A) Alterations in LDHA protein after transfection with siRNA targeting LDHA (si-LDHA) for 48 hours. (B) The impact of JQ1 on cell growth after treatment of si-LDHA. (C) The effects of JQ1 on cellular apoptosis after treatment with si-LDHA (24 hours). (D) The effects of JQ1 on G1 cell cycle arrest after treatment with si-LDHA (24 hours). (E and F) The effects of JQ1 on ATP and lactate production after treatment with si-LDHA (24 hours) (*p < 0.05; **p < 0.01).

Mentions: Given that reduction of LDHA activity by siRNA and small molecule inhibitors could induce oxidative stress and cell death, we further analyzed the role of LDHA in the reduced vitality of ovarian cancer cells being treated by JQ1. We hypothesized that LDHA might be required for accentuating the inhibitive effect of JQ1, and reduced LDHA expression would increase the functional effects of JQ1 in the treatment of ovarian cancer cells. Hence, we selected a specific siRNA to block LDHA expression in Hey cells (Figure 6A). As we expected, reduction of LDHA expression with siRNA markedly decreased cell proliferation (Figure 6B). Treatment with JQ1 at 24 hours after transfection of siRNA partially increased cell viability compared with JQ1 treated cells, which is characterized by partial rescue of cell cycle processes and reduced labeling of Annexin V (Figure 6C and 6D). We then sought to determine whether reduced cellular ATP and lactate production, induced by JQ1, could be rescued by the LDHA knockdown using a specific siRNA. We found that LDHA knockdown mostly suppressed the reduction of cellular ATP and lactate levels after treatment with JQ1 for 24 hours (Figure 6E and 6F). Our results suggest that reduction of LDHA levels or activity by JQ1 triggers cell viability, and that LDHA plays an influential role in the mediation of cell proliferation and metabolism in the JQ1 treated ovarian cancer cells.


JQ1 suppresses tumor growth through downregulating LDHA in ovarian cancer.

Qiu H, Jackson AL, Kilgore JE, Zhong Y, Chan LL, Gehrig PA, Zhou C, Bae-Jump VL - Oncotarget (2015)

JQ1 suppressed cell growth through the downregulation of LDHA(A) Alterations in LDHA protein after transfection with siRNA targeting LDHA (si-LDHA) for 48 hours. (B) The impact of JQ1 on cell growth after treatment of si-LDHA. (C) The effects of JQ1 on cellular apoptosis after treatment with si-LDHA (24 hours). (D) The effects of JQ1 on G1 cell cycle arrest after treatment with si-LDHA (24 hours). (E and F) The effects of JQ1 on ATP and lactate production after treatment with si-LDHA (24 hours) (*p < 0.05; **p < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466659&req=5

Figure 6: JQ1 suppressed cell growth through the downregulation of LDHA(A) Alterations in LDHA protein after transfection with siRNA targeting LDHA (si-LDHA) for 48 hours. (B) The impact of JQ1 on cell growth after treatment of si-LDHA. (C) The effects of JQ1 on cellular apoptosis after treatment with si-LDHA (24 hours). (D) The effects of JQ1 on G1 cell cycle arrest after treatment with si-LDHA (24 hours). (E and F) The effects of JQ1 on ATP and lactate production after treatment with si-LDHA (24 hours) (*p < 0.05; **p < 0.01).
Mentions: Given that reduction of LDHA activity by siRNA and small molecule inhibitors could induce oxidative stress and cell death, we further analyzed the role of LDHA in the reduced vitality of ovarian cancer cells being treated by JQ1. We hypothesized that LDHA might be required for accentuating the inhibitive effect of JQ1, and reduced LDHA expression would increase the functional effects of JQ1 in the treatment of ovarian cancer cells. Hence, we selected a specific siRNA to block LDHA expression in Hey cells (Figure 6A). As we expected, reduction of LDHA expression with siRNA markedly decreased cell proliferation (Figure 6B). Treatment with JQ1 at 24 hours after transfection of siRNA partially increased cell viability compared with JQ1 treated cells, which is characterized by partial rescue of cell cycle processes and reduced labeling of Annexin V (Figure 6C and 6D). We then sought to determine whether reduced cellular ATP and lactate production, induced by JQ1, could be rescued by the LDHA knockdown using a specific siRNA. We found that LDHA knockdown mostly suppressed the reduction of cellular ATP and lactate levels after treatment with JQ1 for 24 hours (Figure 6E and 6F). Our results suggest that reduction of LDHA levels or activity by JQ1 triggers cell viability, and that LDHA plays an influential role in the mediation of cell proliferation and metabolism in the JQ1 treated ovarian cancer cells.

Bottom Line: JQ1, a selective small-molecule BET bromodomain (BRDs) inhibitor, has been found to suppress tumor progression in several cancer cell types.JQ1 reduced both the activity and phosphorylation of LDHA, inhibited lactate production, and decreased the energy supply to ovarian cancer cell lines and tumors.Taken together, our findings suggest that JQ1 is an efficacious anti-tumor agent in ovarian cancer that is associated with cell cycle arrest, induction of apoptosis and alterations of metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Obsterics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.

ABSTRACT
Amplification and overexpression of c-Myc is commonly seen in human ovarian cancers, and this could be a potentially novel therapeutic target for this disease. JQ1, a selective small-molecule BET bromodomain (BRDs) inhibitor, has been found to suppress tumor progression in several cancer cell types. Using ovarian cancer cell lines, a transgenic mouse model, and primary cell cultures from human ovarian cancer tissues, we demonstrated that JQ1 significantly suppressed cellular proliferation and induced cell cycle arrest and apoptosis in ovarian cancer cells and mouse model via targeting c-Myc. In addition, JQ1 had multiple influences on cancer metabolism, particularly in the aerobic glycolysis pathway. JQ1 reduced both the activity and phosphorylation of LDHA, inhibited lactate production, and decreased the energy supply to ovarian cancer cell lines and tumors. Taken together, our findings suggest that JQ1 is an efficacious anti-tumor agent in ovarian cancer that is associated with cell cycle arrest, induction of apoptosis and alterations of metabolism.

Show MeSH
Related in: MedlinePlus