title: Evidence that aberrant protein metabolism contributes to chemoresistance             in multiple myeloma cells.
abstract: Multiple myeloma (MM) is an incurable B lymphocyte cancer. To date, a comparative             analysis of global protein metabolism for the MM cell line CCL-155 (RPMI-8226)             and the non-cancerous B lymphocyte cell line CCL-156 (RPMI‑1788) has not been             published. Here, we report that both global protein synthesis and degradation             occur at a higher rate in MM cells and demonstrate that alkylating agents can             reduce global protein degradation in both cell lines, but the effect is greater             in CCL-156 cells. Treatment with melphalan plus the proteasome inhibitor MG132             reduced global protein degradation for MM cells to roughly 60% of that seen without             drugs, but the reduction was approximately three times greater for CCL-156 cells.             This drug combination was growth inhibitory for both cell lines, but CCL-156 inhibition             was 2-fold greater than that of the MM cell line. Additionally, treatment with             melphalan plus the lysosomal inhibitor chloroquine did not affect growth of MM             cells more than melphalan alone, whereas this combination drastically inhibited             growth of CCL-156 cells despite protein degradation being maintained at 60% level             for both cell lines. This suggests that a lysosomal function other than protein             degradation is required for recovery from alkylation damage in CCL-156 cells.             In general, CCL-156 cells were affected to a greater extent for both protein degradation             and growth inhibition with most drug combinations tested. Statistical analysis             of our data (p=0.066) provides evidence that aberrant proteasome-mediated protein             degradation correlates with chemoresistance in MM cells, but that lysosome-mediated             protein degradation does not.
authors.affiliation: Department of Chemistry and Biochemistry, Eastern Washington                     University, Cheney, WA 99004, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Sipes
authors.forename: Xue
authors.initials: X
authors.lastname: Xia
authors.forename: Brian S
authors.initials: BS
authors.lastname: Lewis
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Burgis
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007976:Leupeptins; D009363:Neoplasm Proteins; D011506:Proteins; D002738:Chloroquine; D046988:Proteasome Endopeptidase Complex; D008558:Melphalan; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde