Inhibition of glycolytic metabolism in glioblastoma cells by Pt3glc combinated with PI3K inhibitor via SIRT3-mediated mitochondrial and PI3K/Akt-MAPK pathway.

Abstract

Glioblastoma multiforme (GBM) is the most malignant and aggressive glioma with abnormal expression of genes that mediate glycolytic metabolism and tumor cell growth. Petunidin-3-O-glucoside (Pt3glc) is a kind of anthocyanin in the red grape and derived beverages, representing the most common naturally occurring anthocyanins with a reduced incidence of cancer and heart diseases. In this study, whether Pt3glc could effectively regulate glycolysis to inhibit GBM cell was investigated by using the DBTRG-05MG cell lines. Notably, Pt3glc displayed potent antiproliferative activity and significantly changed the protein levels related to both glycolytic metabolism and GBM cell survival. The expression of the proapoptotic protein Bcl-2-associated X protein was increased with concomitant reduction on the levels of the antiapoptotic protein B-cell lymphoma 2 and caspase-3 activity. Furthermore, the levels of survival signaling proteins, such as protein kinase B (Akt) and phospho-Akt (Scr473), extracellular signal-regulated kinase (ERK) and phospho-ERK, were significantly decreased by Pt3glc in combination with the phosphoinositide 3-kinase (PI3K) inhibitor of LY294002. Most importantly, the levels of Sirtuin 3 (SIRT3) and phosphorylated p53 were also downregulated, indicating that Pt3glc combinated with PI3K inhibitor could induce GBM cell death may act via the SIRT3/p53-mediated mitochondrial and PI3K/Akt-ERK pathways. Our findings thus provide rational evidence that the combination of Pt3glc with PI3K inhibitor, which target alternative pathways in GBM cells, may be a useful adjuvant therapy in glioblastoma treatment.

• Authors: Gang Wang, Xing-Li Fu, Jun-Jie Wang, Rui Guan, Yan Sun, Shing-Shun Tony To
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 234 Issue 5 Pg. 5888-5903 (05 2019) ISSN: 1097-4652 [Electronic] United States
• PMID: 29336479 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Wiley Periodicals, Inc.

Chemical References

• Anthocyanins
• Apoptosis Regulatory Proteins
• Chromones
• Glucosides
• LY 290042
• Morpholines
• Protein Kinase Inhibitors
• TP53 protein, human
• Tumor Suppressor Protein p53
• petunidin-3-glucoside
• Class I Phosphatidylinositol 3-Kinases
• PIK3CD protein, human
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases
• SIRT3 protein, human
• Sirtuin 3

Topics

• Anthocyanins (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Brain Neoplasms (drug therapy, enzymology, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromones (pharmacology)
• Class I Phosphatidylinositol 3-Kinases (antagonists & inhibitors, genetics, metabolism)
• Glioblastoma (drug therapy, enzymology, genetics, pathology)
• Glucosides (pharmacology)
• Glycolysis (drug effects)
• Humans
• Mitochondria (drug effects, enzymology, genetics, pathology)
• Mitogen-Activated Protein Kinases (metabolism)
• Morpholines (pharmacology)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Sirtuin 3 (genetics, metabolism)
• Tumor Suppressor Protein p53 (metabolism)