When cancer cells develop resistance to chemotherapeutics, it is frequently conferred by the ATPdependent efflux pump P-glycoprotein (MDR1, P-gp, ABCB1). P-gp can efflux a wide range of cancer drugs; thus its expression confers cross-resistance, termed multidrug resistance (MDR), to a wide range of drugs. Strategies to overcome this resistance have been actively sought for over 30 years, yet no clinical solutions exist. A less understood aspect of MDR is the hypersensitivity of resistant cancer cells to other drugs, a phenomenon generally known as collateral sensitivity (CS). This review highlights the extent of this effect for the first time, discusses hypotheses such as ROS generation to account for the underlying generality of this phenomenon, and proposes the exploitation of CS as a strategy to improve response to chemotherapy.

The cell has >60 different farnesylated proteins. Many critically important signal transduction proteins are post-translationally modified with attachment of a farnesyl isoprenoid catalyzed by protein farnesyltransferase (FTase). Recently, it has been shown that farnesyl diphosphate (FPP) analogues can alter the peptide substrate specificity of FTase. We have used combinatorial screening of FPP analogues and peptide substrates to identify patterns in FTase substrate selectivity. Each FPP analogue displays a unique pattern of substrate reactivity with the tested peptides; FTase efficiently catalyzes the transfer of an FPP analogue selectively to one peptide and not another. Furthermore, we have demonstrated that these analogues can enter cells and be incorporated into proteins. These FPP analogues could serve as selective tools to examine the role prenylation plays in individual protein function.Mutant Ras proteins are one of the most important classes of oncogene products and are thus logical targets for cancer chemotherapeutics. Ras, both mutant and normal forms, must be farnesylated by protein farnesyltransferase (FTase) for proper processing, subcellular localization, and thus biological activity (Figure 1). Therefore, significant effort has been focused on the development of small-molecule FTase inhibitors (FTIs) as anticancer, antiRas therapeutics. Two FTIs are in advanced clinical trials (1). The clinical data have demonstrated, however, that FTIs do not function as anti-Ras agents, because K-Ras is alternatively prenylated by geranylgeranyltransferase I upon FTI treatment (23). The cellular (4) and clinical (1) efficacy of FTIs does not correlate with Ras mutational status. The FTI effectiveness observed in non-Ras-positive tumor cells is presumably elicited via inhibition of the farnesylation of other proteins crucial to the growth of tumors. This has led to significant interest in defining the entire set of mammalian prenylated proteins and determining their biological roles (5).Many proteins bearing a Ca 1 a 2 X sequence at their carboxyl terminus are modified by FTase using the C 15 isoprenoid farnesyl diphosphate (FPP) as a co-substrate. Substrate prediction models have estimated that there are >60 farnesylated cellular proteins (67), containing a wide variety of C-terminal sequences, and the inhibition of farnesylation of any individual or a combination of these proteins could be responsible for the antitumor effects of FTI treatment. The investigation of potential "protein-X" FTI targets has uncovered several proteins whose inactivation upon FTI treatment led to profound cellular consequences (8). Correspondingly, the investigation of the role of the farnesyl group on cellular proteins has been aided by the development of FTIs. However, using FTIs to investigate the function of the farnesyl lipid for an individual protein is cumbersome, as they are nonspecific tools. FTIs presumably block the farnesylation of all FTase substrate proteins in mammalian cells. Chemical agents that are capable ...

The expression and function of several multidrug transporters (including ABCB1 and ABCG2) have been studied in human cancer cells and in mouse and human adult stem cells. However, the expression of ABCG2 in human embryonic stem cells (hESCs) remains unclear. Limited and contradictory results in the literature from two research groups have raised questions regarding its expression and function. In this study, we used quantitative real-time PCR, Northern blots, whole genome RNA sequencing, Western blots, and immunofluorescence microscopy to study ABCG2 expression in hESCs. We found that full-length ABCG2 mRNA transcripts are expressed in undifferentiated hESC lines. However, ABCG2 protein was undetectable even under embryoid body differentiation or cytotoxic drug induction. Moreover, surface ABCG2 protein was coexpressed with the differentiation marker SSEA-1 of hESCs, following constant BMP-4 signaling at days 4 and 6. This expression was tightly correlated with the down-regulation of two microRNAs (i.e., hsa-miR-519c and hsa-miR-520h). Transfection of microRNA mimics and inhibitors of these two microRNAs confirmed their direct involvement in the regulation ABCG2 translation. Our findings clarify the controversy regarding the expression of the ABCG2 gene and also provide new insights into translational control of the expression of membrane transporter mRNAs by microRNAs in hESCs.