Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes

Abstract

Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis.

Fig. 1.

Reduced uptake of various radiolabeled compounds was detected in KB-CP20 cells, compared with parental CP-s KB-3-1 cells. [Reprinted from Shen DW, Su A, Liang XJ, Pai-Panandiker A, and Gottesman MM (2004) Reduced expression of small GTPases and hypermethylation of the folate binding protein gene in cisplatin-resistant cells. Br J Cancer 91:270–276.]

Fig. 2.

Schematic illustration of cellular self-defense systems that mediate cisplatin resistance. Cisplatin binds to DNA, triggers the activation or silencing of a number of gene regulatory pathways, such as those related to DNA-damage repair, DNA methylation, histone acetylation, miRNA, EMT, Wnt, transcription factors, and apoptosis, and also inducing gene mutation or deletion. Mislocalization of membrane proteins, such as MRP1, FBP, and TMEM205, largely results from the up-regulation of the transcription factor GCF2, which silences small GTPase rhoA expression, interrupting assembly and or organization of the cytoskeletal actin/filamin network. This in turn results in internalization of several membrane proteins in the intracellular cytoplasm, with decreased influx and accumulation of cisplatin in the CP-r cells. This could also be due to a defective influx route (i.e., reduced endocytosis) or to other putative proteins that are needed for cisplatin uptake. HSPs, Sirt1, ribosomal proteins (RPLs), and GSH-related enzymes may play roles in regulating cellular response and detoxification of the compound. These cell self-defense mechanisms in CP-r cells serve to allow survival and growth of cancer cells exposed to cisplatin.