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Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

View Article: PubMed Central - PubMed

ABSTRACT

Previous studies have demonstrated that the chronic administration of valproic acid (VPA) suppresses angiogenesis in vivo; however, the mechanisms implicated in VPA-induced autophagy remain unclear. The current study aimed to assess VPA-induced autophagy in three prostate cancer cell lines (PC3, DU145 and LNCaP), in addition to analyzing the Akt/mammalian target of rapamycin (mTOR) signal pathway. Prostate cancer cell lines were cultured with various doses of VPA. Cell cycle was analyzed using flow cytometry, and autophagy markers [1A/1B-light chain 3 (LC3)-II and Beclin-1] were examined using transmission electron microscopy, fluorescent microscopy and western blotting. Activation of the Akt/mTOR signal pathway was also assessed by western blotting. The results demonstrated that VPA induced autophagosomes and suppressed the Akt/mTOR signal pathway. This was confirmed by detection of increased LC3-II and Beclin-1 in VPA-treated cells compared with untreated controls. Phosphorylated forms of Akt (PC3, P=0.048; DU145, P=0.045; LNCaP, P=0.039) and mTOR (PC3, P=0.012; DU145, P=0.41; LNCaP, P=0.35) were significantly reduced following VPA treatment. These results suggest that VPA may function as a histone deacetylase inhibitor, suppressing the growth of prostate cancer cells by modulating autophagy pathways, including inhibition of the Akt/mTOR pathway. Further experiments are required to determine the significance of all involved pathways regarding VPA-induced growth inhibition.

No MeSH data available.


Related in: MedlinePlus

Ultrastructure of autophagy observed by electron microscopy in prostate cancer cells following treatment with valproic acid (0, 2.5 and 5.0 mM). Different sizes and stages of autophagic vacuoles were visible at a ×1,000 magnification. Numerous autophagic lysosomes (arrowheads) were observed in the (A) PC3, (B) DU145 and (C) LNCaP cells. The majority of autophagic lysosomes were identified in the late autophagic stages.
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f2-ol-0-0-4880: Ultrastructure of autophagy observed by electron microscopy in prostate cancer cells following treatment with valproic acid (0, 2.5 and 5.0 mM). Different sizes and stages of autophagic vacuoles were visible at a ×1,000 magnification. Numerous autophagic lysosomes (arrowheads) were observed in the (A) PC3, (B) DU145 and (C) LNCaP cells. The majority of autophagic lysosomes were identified in the late autophagic stages.

Mentions: Scanning electron micrographs illustrated that following treatment with VPA, autophagosomes formed inside the cytoplasm of the prostate cancer cells and appeared to contain cellular organelles (Fig. 2). Micrographs demonstrated that the control group exhibited normal organelle morphology. Autophagic vesicles and autolysosomes were observed in organelles, including the mitochondria, endoplasmic reticulum and cytoplasmic materials, in the cells treated with VPA. At the initiation of cell autophagy in all three cell lines, numerous smooth endoplasmic reticulum-like isolation membranes were observed, which formed portions of the cytosol. These double-membrane structures allow the fusion of autophagosomes with lysosomes, resulting in the formation of autophagic lysosomes (12). Finally, the majority of mitochondria and other organelles had disappeared from the cells, and remnants of organelles were identified in the autophagic lysosomes of VPA-treated cells whose nuclear chromatin had condensed into small, irregular masses.


Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells
Ultrastructure of autophagy observed by electron microscopy in prostate cancer cells following treatment with valproic acid (0, 2.5 and 5.0 mM). Different sizes and stages of autophagic vacuoles were visible at a ×1,000 magnification. Numerous autophagic lysosomes (arrowheads) were observed in the (A) PC3, (B) DU145 and (C) LNCaP cells. The majority of autophagic lysosomes were identified in the late autophagic stages.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4998110&req=5

f2-ol-0-0-4880: Ultrastructure of autophagy observed by electron microscopy in prostate cancer cells following treatment with valproic acid (0, 2.5 and 5.0 mM). Different sizes and stages of autophagic vacuoles were visible at a ×1,000 magnification. Numerous autophagic lysosomes (arrowheads) were observed in the (A) PC3, (B) DU145 and (C) LNCaP cells. The majority of autophagic lysosomes were identified in the late autophagic stages.
Mentions: Scanning electron micrographs illustrated that following treatment with VPA, autophagosomes formed inside the cytoplasm of the prostate cancer cells and appeared to contain cellular organelles (Fig. 2). Micrographs demonstrated that the control group exhibited normal organelle morphology. Autophagic vesicles and autolysosomes were observed in organelles, including the mitochondria, endoplasmic reticulum and cytoplasmic materials, in the cells treated with VPA. At the initiation of cell autophagy in all three cell lines, numerous smooth endoplasmic reticulum-like isolation membranes were observed, which formed portions of the cytosol. These double-membrane structures allow the fusion of autophagosomes with lysosomes, resulting in the formation of autophagic lysosomes (12). Finally, the majority of mitochondria and other organelles had disappeared from the cells, and remnants of organelles were identified in the autophagic lysosomes of VPA-treated cells whose nuclear chromatin had condensed into small, irregular masses.

View Article: PubMed Central - PubMed

ABSTRACT

Previous studies have demonstrated that the chronic administration of valproic acid (VPA) suppresses angiogenesis in vivo; however, the mechanisms implicated in VPA-induced autophagy remain unclear. The current study aimed to assess VPA-induced autophagy in three prostate cancer cell lines (PC3, DU145 and LNCaP), in addition to analyzing the Akt/mammalian target of rapamycin (mTOR) signal pathway. Prostate cancer cell lines were cultured with various doses of VPA. Cell cycle was analyzed using flow cytometry, and autophagy markers [1A/1B-light chain 3 (LC3)-II and Beclin-1] were examined using transmission electron microscopy, fluorescent microscopy and western blotting. Activation of the Akt/mTOR signal pathway was also assessed by western blotting. The results demonstrated that VPA induced autophagosomes and suppressed the Akt/mTOR signal pathway. This was confirmed by detection of increased LC3-II and Beclin-1 in VPA-treated cells compared with untreated controls. Phosphorylated forms of Akt (PC3, P=0.048; DU145, P=0.045; LNCaP, P=0.039) and mTOR (PC3, P=0.012; DU145, P=0.41; LNCaP, P=0.35) were significantly reduced following VPA treatment. These results suggest that VPA may function as a histone deacetylase inhibitor, suppressing the growth of prostate cancer cells by modulating autophagy pathways, including inhibition of the Akt/mTOR pathway. Further experiments are required to determine the significance of all involved pathways regarding VPA-induced growth inhibition.

No MeSH data available.


Related in: MedlinePlus