Monocytic differentiation and synthesis of proteins associated with apoptosis in human leukemia U-937 cells acquiring resistance to vincristine.
Human leukemia U-937/WT cells were exposed to stepwise increased concentrations of Vincristine so that Vincristine-resistant cell sublines (termed U-937/RV) were developed. Established U-937/RV cell sublines have continuously propagated over a year, both in absence and presence of VCR, and have demonstrated similar features. In contrast to U-937/WT cells, U-937/RV cells have longer doubling time, and are more differentiated as determined by appearance of distinct morphological features and synthesis of mRNA that codes for the monocyte colony-stimulating factor-1 receptor (c-fms). Both apoptosis-suppressing Bcl-2 and Bcl-XL proteins were undectable in U-937/WT cells, whereas Bcl-2 was nearly detectable and Bcl-XL readily detectable in U-937/RV cells. The apoptosis-promoting Bax protein was also absent in U-937/WT cells and readily detected in U-937/RV cells. Vincristine-resistant cells with different levels of resistance synthesize similar levels of c-fms mRNA and Bax protein. Finally, unlike U-937/WT cells, U-937/RV cells have no ability to induce tumors when xenografted in immunodeficient mice. The findings collectively suggest that development of resistance to Vincristine in U-937/WT cells may correlate with cell differentiation and synthesis of proteins that regulate apoptosis.
Pantazis
P
P
Stehlin Foundation for Cancer Research, St Joseph Hospital, Houston, TX 77003, USA. ppant@pipeline.com
Chatterjee
D
D
Han
Z
Z
Wyche
J
J
DeJesus
A
A
Giovanella
B
B
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000378:metabolism / Q000473:pathology*; D009368:Neoplasm Transplantation; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000096:biosynthesis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494826:BAX protein, human; C494811:BCL2L1 protein, human; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D014750:Vincristine; D016186:Receptor, Macrophage Colony-Stimulating Factor