Imatinib‑induced apoptosis of gastric cancer cells is mediated by endoplasmic reticulum stress.

Abstract

Imatinib is a powerful tyrosine kinase inhibitor that specifically targets BCR‑ABL, c‑KIT, and PDGFR kinases, and is used in the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors, and other types of cancers. However, the possible anticancer effects of imatinib in gastric cancer have not yet been explored. The present study evaluated the in vitro effects of imatinib on gastric cancer cells and determined the molecular mechanism underlying these effects. We determined that imatinib induced mitochondria‑mediated apoptosis of gastric cancer cells by involving endoplasmic reticulum (ER) stress‑associated activation of c‑Jun NH2‑terminal kinase (JNK). We also found that imatinib suppressed cell proliferation in a time‑ and dose‑dependent manner. Cell cycle analysis revealed that imatinib‑treated AGS cells were arrested in the G2/M phase of the cell cycle. Moreover, imatinib‑treated cells exhibited increased levels of phosphorylated JNK, and of the transcription factor C/EBP homologous protein, an ER stress‑associated apoptotic molecule. Results of cell viability assays revealed that treatment with a combination of imatinib and chemotherapy agents irinotecan or 5‑Fu synergistically inhibited cell growth, compared with treatment with any of these drugs alone. These data indicated that imatinib exerted cytotoxic effects on gastric cancer cells by inducing apoptosis mediated by reactive oxygen species generation and ER stress‑associated JNK activation. Furthermore, we revealed that imatinib induced the apoptosis of gastric cancer cells by inhibiting platelet‑derived growth factor receptor signaling. Collectively, our results strongly support the use of imatinib in the treatment of treating gastric cancer.

• Authors: Jung Lim Kim, Dae-Hee Lee, Soyeon Jeong, Bo Ram Kim, Yoo Jin Na, Seong Hye Park, Min Jee Jo, Yoon A Jeong, Sang Cheul Oh
• Journal: Oncology reports (Oncol Rep) Vol. 41 Issue 3 Pg. 1616-1626 (Mar 2019) ISSN: 1791-2431 [Electronic] Greece
• PMID: 30569109 (Publication Type: Journal Article)

Chemical References

• DDIT3 protein, human
• Protein Kinase Inhibitors
• Reactive Oxygen Species
• Transcription Factor CHOP
• Irinotecan
• Imatinib Mesylate
• Receptors, Platelet-Derived Growth Factor
• ERN1 protein, human
• Protein Serine-Threonine Kinases
• JNK Mitogen-Activated Protein Kinases
• Endoribonucleases
• Fluorouracil

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation
• Drug Synergism
• Endoplasmic Reticulum Stress (drug effects)
• Endoribonucleases (metabolism)
• Fluorouracil (pharmacology, therapeutic use)
• Humans
• Imatinib Mesylate (pharmacology, therapeutic use)
• Irinotecan (pharmacology, therapeutic use)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein Serine-Threonine Kinases (metabolism)
• Reactive Oxygen Species (metabolism)
• Receptors, Platelet-Derived Growth Factor (metabolism)
• Signal Transduction (drug effects)
• Stomach Neoplasms (drug therapy, pathology)
• Transcription Factor CHOP (metabolism)