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Reduced expression of AMPK-β1 during tumor progression enhances the oncogenic capacity of advanced ovarian cancer.

Li C, Liu VW, Chiu PM, Yao KM, Ngan HY, Chan DW - Mol. Cancer (2014)

Bottom Line: AMP-activated protein kinase (AMPK) is a key energy sensor that is involved in regulating cell metabolism.Functionally, enforced expression of AMPK-β1 inhibited ovarian-cancer-cell proliferation, anchorage-independent cell growth, cell migration and invasion.Taken together, these findings suggest that the reduced expression of AMPK-β1 confers lower AMPK activity, which enhances the oncogenic capacity of advanced-stage ovarian cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics & Gynecology, The University of Hong Kong, 6th Floor, Professorial Block, Queen Mary Hospital, Pokfulam, Hong Kong, SAR, People's Republic of China. hysngan@hku.hk.

ABSTRACT
AMP-activated protein kinase (AMPK) is a key energy sensor that is involved in regulating cell metabolism. Our previous study revealed that the subunits of the heterotimeric AMPK enzyme are diversely expressed during ovarian cancer progression. However, the impact of the variable expression of these AMPK subunits in ovarian cancer oncogenesis remains obscure. Here, we provide evidence to show that reduced expression of the AMPK-β1 subunit during tumor progression is associated with the increased oncogenic capacity of advanced ovarian cancer cells. Immunohistochemical analysis revealed that AMPK-β1 levels were reduced in advanced-stage (P = 0.008), high-grade (P = 0.013) and metastatic ovarian cancers (P = 0.008). Intriguingly, down-regulation of AMPK-β1 was progressively reduced from tumor stages 1 to 3 of ovarian cancer. Functionally, enforced expression of AMPK-β1 inhibited ovarian-cancer-cell proliferation, anchorage-independent cell growth, cell migration and invasion. Conversely, depletion of AMPK-β1 by siRNA enhanced the oncogenic capacities of ovarian cancer cells, suggesting that the loss of AMPK-β1 favors the aggressiveness of ovarian cancer. Mechanistically, enforced expression of AMPK-β1 increased AMPK activity, which, in turn, induced cell-cycle arrest via inhibition of AKT/ERK signaling activity as well as impaired cell migration/invasion through the suppression of JNK signaling in ovarian cancer cells. Taken together, these findings suggest that the reduced expression of AMPK-β1 confers lower AMPK activity, which enhances the oncogenic capacity of advanced-stage ovarian cancer.

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AMPK-β1 regulates cell migration and invasion of ovarian cancer cells. Enhanced expression of AMPK-β1 in SKOV3 (C1 and C3) cells resulted in a reduced cell migratory rate (3 to 3.5-fold) using (A) the transwell cell migration assay (P < 0.005) and a 3.5-fold decrease in the cell invasive rate using (B) the transwell cell invasion assay (P < 0.001). Conversely, depletion of endogenous AMPK-β1 in OVCA433 (C1 and C12) by shRNA knockdown enhanced the cell migration rate by 8- to 12-fold using (C) the transwell cell migration assay (P < 0.001) and resulted in a 7- to 12-fold increase in the cell invasive rate using (D) the transwell cell invasion assay (P < 0.0001). V1 and V2 are the empty vector controls for OVCA433 and SKOV3, respectively.
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Figure 4: AMPK-β1 regulates cell migration and invasion of ovarian cancer cells. Enhanced expression of AMPK-β1 in SKOV3 (C1 and C3) cells resulted in a reduced cell migratory rate (3 to 3.5-fold) using (A) the transwell cell migration assay (P < 0.005) and a 3.5-fold decrease in the cell invasive rate using (B) the transwell cell invasion assay (P < 0.001). Conversely, depletion of endogenous AMPK-β1 in OVCA433 (C1 and C12) by shRNA knockdown enhanced the cell migration rate by 8- to 12-fold using (C) the transwell cell migration assay (P < 0.001) and resulted in a 7- to 12-fold increase in the cell invasive rate using (D) the transwell cell invasion assay (P < 0.0001). V1 and V2 are the empty vector controls for OVCA433 and SKOV3, respectively.

Mentions: We also studied the functional role of AMPK-β1 in ovarian cancer cell migration and invasion. Using transwell migration and invasion assays, enhanced AMPK-β1 expression was found to significantly attenuate the cell migration (P < 0.005) and invasive (P < 0.001) capacities of SKOV3 stable clones (CC1 and C3) (Figure 4A and B). In contrast, stable depletion of endogenous AMPK-β1 in AMPK-β1-expressing OVCA433 cells (C1 and C12) using the sh-β1 shRNA enhanced cell migration (P < 0.001) and invasion (P < 0.0001) (Figure 4C and D). These results indicate that down-regulation of AMPK-β1 enhances the aggressiveness of ovarian cancer and explains why its level is progressively decreased in advanced stage and high-grade ovarian cancers.


Reduced expression of AMPK-β1 during tumor progression enhances the oncogenic capacity of advanced ovarian cancer.

Li C, Liu VW, Chiu PM, Yao KM, Ngan HY, Chan DW - Mol. Cancer (2014)

AMPK-β1 regulates cell migration and invasion of ovarian cancer cells. Enhanced expression of AMPK-β1 in SKOV3 (C1 and C3) cells resulted in a reduced cell migratory rate (3 to 3.5-fold) using (A) the transwell cell migration assay (P < 0.005) and a 3.5-fold decrease in the cell invasive rate using (B) the transwell cell invasion assay (P < 0.001). Conversely, depletion of endogenous AMPK-β1 in OVCA433 (C1 and C12) by shRNA knockdown enhanced the cell migration rate by 8- to 12-fold using (C) the transwell cell migration assay (P < 0.001) and resulted in a 7- to 12-fold increase in the cell invasive rate using (D) the transwell cell invasion assay (P < 0.0001). V1 and V2 are the empty vector controls for OVCA433 and SKOV3, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4016028&req=5

Figure 4: AMPK-β1 regulates cell migration and invasion of ovarian cancer cells. Enhanced expression of AMPK-β1 in SKOV3 (C1 and C3) cells resulted in a reduced cell migratory rate (3 to 3.5-fold) using (A) the transwell cell migration assay (P < 0.005) and a 3.5-fold decrease in the cell invasive rate using (B) the transwell cell invasion assay (P < 0.001). Conversely, depletion of endogenous AMPK-β1 in OVCA433 (C1 and C12) by shRNA knockdown enhanced the cell migration rate by 8- to 12-fold using (C) the transwell cell migration assay (P < 0.001) and resulted in a 7- to 12-fold increase in the cell invasive rate using (D) the transwell cell invasion assay (P < 0.0001). V1 and V2 are the empty vector controls for OVCA433 and SKOV3, respectively.
Mentions: We also studied the functional role of AMPK-β1 in ovarian cancer cell migration and invasion. Using transwell migration and invasion assays, enhanced AMPK-β1 expression was found to significantly attenuate the cell migration (P < 0.005) and invasive (P < 0.001) capacities of SKOV3 stable clones (CC1 and C3) (Figure 4A and B). In contrast, stable depletion of endogenous AMPK-β1 in AMPK-β1-expressing OVCA433 cells (C1 and C12) using the sh-β1 shRNA enhanced cell migration (P < 0.001) and invasion (P < 0.0001) (Figure 4C and D). These results indicate that down-regulation of AMPK-β1 enhances the aggressiveness of ovarian cancer and explains why its level is progressively decreased in advanced stage and high-grade ovarian cancers.

Bottom Line: AMP-activated protein kinase (AMPK) is a key energy sensor that is involved in regulating cell metabolism.Functionally, enforced expression of AMPK-β1 inhibited ovarian-cancer-cell proliferation, anchorage-independent cell growth, cell migration and invasion.Taken together, these findings suggest that the reduced expression of AMPK-β1 confers lower AMPK activity, which enhances the oncogenic capacity of advanced-stage ovarian cancer.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Obstetrics & Gynecology, The University of Hong Kong, 6th Floor, Professorial Block, Queen Mary Hospital, Pokfulam, Hong Kong, SAR, People's Republic of China. hysngan@hku.hk.

ABSTRACT
AMP-activated protein kinase (AMPK) is a key energy sensor that is involved in regulating cell metabolism. Our previous study revealed that the subunits of the heterotimeric AMPK enzyme are diversely expressed during ovarian cancer progression. However, the impact of the variable expression of these AMPK subunits in ovarian cancer oncogenesis remains obscure. Here, we provide evidence to show that reduced expression of the AMPK-β1 subunit during tumor progression is associated with the increased oncogenic capacity of advanced ovarian cancer cells. Immunohistochemical analysis revealed that AMPK-β1 levels were reduced in advanced-stage (P = 0.008), high-grade (P = 0.013) and metastatic ovarian cancers (P = 0.008). Intriguingly, down-regulation of AMPK-β1 was progressively reduced from tumor stages 1 to 3 of ovarian cancer. Functionally, enforced expression of AMPK-β1 inhibited ovarian-cancer-cell proliferation, anchorage-independent cell growth, cell migration and invasion. Conversely, depletion of AMPK-β1 by siRNA enhanced the oncogenic capacities of ovarian cancer cells, suggesting that the loss of AMPK-β1 favors the aggressiveness of ovarian cancer. Mechanistically, enforced expression of AMPK-β1 increased AMPK activity, which, in turn, induced cell-cycle arrest via inhibition of AKT/ERK signaling activity as well as impaired cell migration/invasion through the suppression of JNK signaling in ovarian cancer cells. Taken together, these findings suggest that the reduced expression of AMPK-β1 confers lower AMPK activity, which enhances the oncogenic capacity of advanced-stage ovarian cancer.

Show MeSH
Related in: MedlinePlus