Proteomic analysis of multidrug-resistance mechanisms in adriamycin-resistant variants of DLKP, a squamous lung cancer cell line

Alterations in protein expression associated with adriamycin resistance in a panel of variants derived from the poorly differentiated squamous cell lung carcinoma DLKP were investigated using 2-D DIGE. Of the 80 proteins identified as being differentially expressed, 32 correlated to adriamycin resistance. Twenty-four proteins showed positive correlations with drug resistance, 11 correlated directly with increase in the resistance (including NDPK, RPA2, CCT2, HSP70 and Annexin A1) while 13 proteins (including HNRP K and H1, aldehyde dehydrogenase (ALDH), stomatin and CCT3) increased to a similar level in all drug-resistant variants. Fewer proteins showed an inverse correlation with resistance; two (protein disulphide isomerase (PDI) and HSP70 variant 1) displayed a similar decrease in all variants and six (including prohibitin (PHB) and EIF5A) correlated inversely with resistance. Three proteins (EEF1D, Actin G1 and Annexin 1) correlated with the invasive status of these variants. Some expected targets of adriamycin action showed correlation with resistance including RPA2 (critical for DNA damage repair), while others proteins involved in protection from ROS production (such as GST, peroxiredoxins and thioredoxins) did not. The proteomic analysis revealed a large number of changes in protein expression that may contribute to a more apoptosis-resistant state. Many of these changes could provide novel targets for overcoming resistance.