Development of Resistance to Endoplasmic Reticulum Stress-Inducing Agents in Mouse Leukemic L1210 Cells

Four new variants of L1210 cells resistant to endoplasmic reticulum (ER) stressors, tunicamycin (S(Tun)), thapsigargin (S(Thap)), bortezomib (S(Bor)), and MG-132 (S(MG-132)), were developed via an 18-month periodic cultivation in culture medium with a gradual increase in substance concentration. Multidrug resistance was generated for S(Tun) (to tunicamycin, bortezomib and MG-132), S(Thap) (to tunicamycin, thapsigargin and MG-132), S(Bor) (to bortezomib and MG-132), and S(MG-132) (to bortezomib and MG-132). These cells were compared to the original L1210 cells and another two variants, which expressed P-gp due to induction with vincristine or transfection with the gene encoding P-gp, in terms of the following properties: sensitivity to either vincristine or the ER stressors listed above, proliferative activity, expression of resistance markers and proteins involved in the ER stress response, and proteasome activity. The resistance of the new cell variants to ER stressors was accompanied by a decreased proliferation rate and increased proteasome activity. The most consistent change in protein expression was the elevation of GRP78/BiP at the mRNA and protein levels in all resistant variants of L1210 cells. In conclusion, the mechanisms of resistance to these stressors have certain common features, but there are also specific differences.