Farnesyltransferase inhibitor tipifarnib inhibits Rheb prenylation and stabilizes Bax in acute myelogenous leukemia cells.

Abstract

Although farnesyltransferase inhibitors have shown promising activity in relapsed lymphoma and sporadic activity in acute myelogenous leukemia, their mechanism of cytotoxicity is incompletely understood, making development of predictive biomarkers difficult. In the present study, we examined the action of tipifarnib in human acute myelogenous leukemia cell lines and clinical samples. In contrast to the Ras/MEK/ERK pathway-mediated Bim upregulation that is responsible for tipifarnib-induced killing of malignant lymphoid cells, inhibition of Rheb-induced mTOR signaling followed by dose-dependent upregulation of Bax and Puma occurred in acute myelogenous leukemia cell lines undergoing tipifarnib-induced apoptosis. Similar Bax and Puma upregulation occurred in serial bone marrow samples harvested from a subset of acute myelogenous leukemia patients during tipifarnib treatment. Expression of FTI-resistant Rheb M184L, like knockdown of Bax or Puma, diminished tipifarnib-induced killing. Further analysis demonstrated that increased Bax and Puma levels reflect protein stabilization rather than increased gene expression. In U937 cells selected for tipifarnib resistance, neither inhibition of signaling downstream of Rheb nor Bax and Puma stabilization occurred. Collectively, these results not only identify a pathway downstream from Rheb that contributes to tipifarnib cytotoxicity in human acute myelogenous leukemia cells, but also demonstrate that FTI-induced killing of lymphoid versus myeloid cells reflects distinct biochemical mechanisms downstream of different farnesylated substrates. (ClinicalTrials.gov identifier NCT00602771).

• Authors: Husheng Ding, Jennifer S McDonald, Seongseok Yun, Paula A Schneider, Kevin L Peterson, Karen S Flatten, David A Loegering, Ann L Oberg, Shaun M Riska, Shengbing Huang, Frank A Sinicrope, Alex A Adjei, Judith E Karp, X Wei Meng, Scott H Kaufmann
• Journal: Haematologica (Haematologica) Vol. 99 Issue 1 Pg. 60-9 (Jan 2014) ISSN: 1592-8721 [Electronic] Italy
• PMID: 23996484 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BBC3 protein, human
• Neuropeptides
• Proto-Oncogene Proteins
• Quinolones
• RHEB protein, human
• Ras Homolog Enriched in Brain Protein
• bcl-2-Associated X Protein
• Farnesyltranstransferase
• TOR Serine-Threonine Kinases
• Monomeric GTP-Binding Proteins
• tipifarnib

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (genetics)
• Farnesyltranstransferase (antagonists & inhibitors, metabolism)
• Humans
• Leukemia, Myeloid, Acute (metabolism)
• Monomeric GTP-Binding Proteins (metabolism)
• Neuropeptides (metabolism)
• Prenylation (drug effects)
• Protein Stability (drug effects)
• Proto-Oncogene Proteins (metabolism)
• Quinolones (pharmacology)
• Ras Homolog Enriched in Brain Protein
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• U937 Cells
• bcl-2-Associated X Protein (metabolism)