Involvement of MCL1, c-myc, and cyclin D2 protein degradation in ponatinib-induced cytotoxicity against T315I(+) Ph+leukemia cells.

Abstract

T315I mutation found in chronic myelogenous leukemia (CML) and Ph + ALL patients is the most serious one among resistance against BCR/ABL kinase inhibitors including imatinib and is only responsive to ponatinib (PNT). However, the novel strategy is required to reduce life-threatening adverse effects of PNT including ischemic cardiovascular disease. We examined the mechanism of PNT-induced cytotoxicity against a T315I(+) Ph + ALL cell line, TccY/Sr. PNT induced apoptosis (increased sub G1 cells, and cleaved caspase3 and PARP), and suppressed protein expression of MCL1, cyclin D2 and c-myc, which were reversed by a proteasome inhibitor, MG132, suggesting enhanced proteasomal degradation by PNT. Among BCL2 family inhibitors, MCL1 inhibitors (maritoclax and AZD5991) robustly induced cell death, showing the MCL1-dependent survival of TccY/Sr cells. Decreased MCL1 and c-myc expression by PNT was also observed in T315I(+) MEGA2/STIR cells. PNT suppressed PI3K activation followed by AKT inhibition and GSK3 dephosphorylation. PI3K/AKT inhibitors mimicked PNT, suggesting that PI3K/AKT signaling is important for survival of TccY/Sr cells. Moreover, GSK3 inhibitor (SB216763) reduced PNT-induced cytotoxicity and degradation of c-myc and MCL1. AZD5991 exhibited the synergistic action with PNT, anti-cancer drugs and venetoclax (BCL2 inhibitor), suggesting the utility of MCL1 inhibitor alone or in combination as a future clinical option for Ph + leukemia patients.

• Authors: Chisato Inoue, Sayaka Sobue, Yoshiyuki Kawamoto, Yuji Nishizawa, Masatoshi Ichihara, Akihiro Abe, Fumihiko Hayakawa, Motoshi Suzuki, Yoshinori Nozawa, Takahsi Murate
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 525 Issue 4 Pg. 1074-1080 (05 14 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 32184020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• AZD5991
• Antineoplastic Agents
• CCND2 protein, human
• Cyclin D2
• Imidazoles
• Leupeptins
• MCL1 protein, human
• MYC protein, human
• Macrocyclic Compounds
• Myeloid Cell Leukemia Sequence 1 Protein
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-myc
• Pyridazines
• Pyrroles
• marinopyrrole A
• ponatinib
• Imatinib Mesylate
• Glycogen Synthase Kinase 3
• Protein Phosphatase 2
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde
• Wortmannin

Topics

• Antineoplastic Agents (pharmacology)
• Cell Death (drug effects, genetics)
• Cell Line, Tumor
• Cyclin D2 (genetics, metabolism)
• Drug Resistance, Neoplasm (genetics)
• Drug Synergism
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Humans
• Imatinib Mesylate (pharmacology)
• Imidazoles (pharmacology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism)
• Leupeptins (pharmacology)
• Macrocyclic Compounds (pharmacology)
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors, genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism, pharmacology)
• Phosphoinositide-3 Kinase Inhibitors (pharmacology)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Protein Phosphatase 2 (metabolism)
• Proteolysis (drug effects)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Pyridazines (pharmacology)
• Pyrroles (pharmacology)
• Signal Transduction (drug effects, genetics)
• Wortmannin (pharmacology)