RRC ID 45482
Author Tanaka T, Kitajima Y, Miyake S, Yanagihara K, Hara H, Nishijima-Matsunobu A, Baba K, Shida M, Wakiyama K, Nakamura J, Noshiro H.
Title The Apoptotic Effect of HIF-1α Inhibition Combined with Glucose plus Insulin Treatment on Gastric Cancer under Hypoxic Conditions.
Journal PLoS ONE
Abstract Gastric cancer grows under a hypoxic environment. HIF-1α is known to play an important role in controlling the production of reactive oxygen species (ROS) in the mitochondria under hypoxic conditions. We previously established HIF-1α knockdown (KD) cells and control (SC) cells in the 58As9 gastric cancer cell line. In this study, we revealed that KD cells, but not SC cells, induced apoptosis under conditions of hypoxia (1% O2) due to excessive production of ROS. A quantitative RT-PCR analysis demonstrated that the expressions of ten genes, which are involved in the control mechanisms of ROS (including the Warburg effect, mitophagy, electron transport chain [ETC] modification and ROS scavenging), were regulated by HIF-1α. Moreover, the promotion of glucose uptake by glucose plus insulin (GI) treatment enhanced the apoptotic effect, which was accompanied by further ROS production in hypoxic KD cells. A Western blot analysis showed that the membranous expression of GLUT1 in KD cells was elevated by glucose and/or insulin treatments, indicating that the GI-induced glucose uptake is mediated by the increased translocation of GLUT1 on the cell membrane. Finally, the anti-tumor effect of HIF-1α knockdown (KD) plus GI was evaluated using a tumor xenograft model, where a hypoxic environment naturally exists. As a result, the GI treatment strongly inhibited the growth of the KD tumors whereby cell apoptosis was highly induced in comparison to the control treatment. In contrast, the growth of the SC tumors expressing HIF-1α was not affected by the GI treatment. Taken together, the results suggest that HIF-1α inhibition plus GI may be an ideal therapy, because the apoptosis due to the destruction of ROS homeostasis is specifically induced in gastric cancer that grows under a hypoxic environment, but not in the normal tissue under the aerobic conditions.
Volume 10(9)
Pages e0137257
Published 2015
DOI 10.1371/journal.pone.0137257
PII PONE-D-15-16624
PMID 26339797
PMC PMC4560388
MeSH Animals Apoptosis / drug effects Cell Hypoxia Cell Line, Tumor Female Gene Expression Regulation, Neoplastic* Gene Knockdown Techniques Glucose / pharmacology* Glucose Transporter Type 1 / genetics Glucose Transporter Type 1 / metabolism Humans Hypoxia / drug therapy* Hypoxia / genetics Hypoxia / metabolism Hypoxia / pathology Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors* Hypoxia-Inducible Factor 1, alpha Subunit / genetics Hypoxia-Inducible Factor 1, alpha Subunit / metabolism Insulin / pharmacology* Mice Mice, Nude Neoplasm Proteins / genetics Neoplasm Proteins / metabolism Oxygen / pharmacology RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Reactive Oxygen Species / agonists Reactive Oxygen Species / metabolism Signal Transduction Stomach Neoplasms / drug therapy* Stomach Neoplasms / genetics Stomach Neoplasms / metabolism Stomach Neoplasms / pathology Vascular Endothelial Growth Factor A / genetics Vascular Endothelial Growth Factor A / metabolism Xenograft Model Antitumor Assays
IF 2.776
Times Cited 4
Human and Animal Cells