A 22 kDa Calcium-Binding Protein, Sorcin, is Encoded by Amplified Genes in Multidrug-Resistant Cells

Abstract

A multidrug-resistant (mdr) cell is one which is selected for resistance to a single agent and is simultaneously cross-resistant to a variety of other drugs. The cells described in this overview were selected for resistance to such natural product cancer drugs as vincristine, adriamycin, or actinomycin D (Biedler and Peterson 1981). Cellular cross-resistance to agents with such diverse molecular structures and such varied cellular mechanisms of toxic action, as characterize the drugs in this category, is both interesting and perplexing. Development of multidrug resistance frequently occurs in cancer patients being treated with chemotherapy and is a major factor in the failure of drug treatment. The need to overcome or circumvent clinical drug resistance is the motivation for the vigorous studies of multidrug resistance being conducted in many laboratories all over the world (Bradley et al. 1988; Tsuruo 1988; Biedler and Meyers 1989; Ling 1989). A number of biochemical and phenotypic characteristics have been shown to be associated with resistance development in cultured cells. The most common characteristic is overproduction of a plasma membrane protein called P-glycoprotein (Pgp). Various molecular weights of Pgp have been reported, the most common one being 170000 (Endicott and Ling 1989). The deduced amino acid sequence and hydropathy plot information for Pgp suggests that the glycoprotein has an ion channel-type structure (Ling 1989). Pgp can associate with or bind to a number of drugs in the multidrug resistance category as well as to other substances including progesterone and calcium channel blockers (Safa et al. 1986; Yang et al. 1989; Safa et al. 1987). This binding capability may be part of the putative function of Pgp as an efflux pump for these substances. Effective removal of drugs from intracellular compartments may be a major mechanism of resistance in cells with increased production of Pgp. Many cell lines have elevated levels of Pgp protein as a result of amplification of Pgp genes (Riordan et al. 1985). There are two human Pgp genes and three each in hamster and mouse cells (Ng et al. 1989). The Pgp genes are part of an amplifiable domain, or amplicon, which includes five other genes. One of these other genes encodes a protein named sorcin (soluble resistance-related calcium-binding protein) (Van der Bliek et al. 1986a; Meyers et al. 1987; Van der Bliek et al. 1988).