Roles of Sorcin in Drug Resistance in Cancer: One Protein, Many Mechanisms, for a Novel Potential Anticancer Drug Target

Abstract

The development of drug resistance is one of the main causes of failure in anti-cancer treatments. Tumor cells adopt many strategies to counteract the action of chemotherapeutic agents, e.g., enhanced DNA damage repair, inactivation of apoptotic pathways, alteration of drug targets, drug inactivation, and overexpression of ABC (Adenosine triphosphate-binding cassette, or ATP-binding cassette) transporters. These are broad substrate-specificity ATP-dependent efflux pumps able to export toxins or drugs out of cells; for instance, ABCB1 (MDR1, or P-glycoprotein 1), overexpressed in most cancer cells, confers them multidrug resistance (MDR). The gene coding for sorcin (SOluble Resistance-related Calcium-binding proteIN) is highly conserved among mammals and is located in the same chromosomal locus and amplicon as the ABC transporters ABCB1 and ABCB4, both in human and rodent genomes (two variants of ABCB1, i.e., ABCB1a and ABCB1b, are in rodent amplicon). Sorcin was initially characterized as a soluble protein overexpressed in multidrug (MD) resistant cells and named "resistance-related" because of its co-amplification with ABCB1. Although for years sorcin overexpression was thought to be only a by-product of the co-amplification with ABC transporter genes, many papers have recently demonstrated that sorcin plays an important part in MDR, indicating a possible role of sorcin as an oncoprotein. The present review illustrates sorcin roles in the generation of MDR via many mechanisms and points to sorcin as a novel potential target of different anticancer molecules.

Keywords: ABCB1; calcium; cancers; chemotherapeutic drugs; endoplasmic reticulum; multidrug resistance; sorcin.

Figure 1

Upon administration of chemotherapeutic drugs, intrinsic or extrinsic factors determine multidrug resistance (MDR). These include absorption, distribution, metabolism, and elimination (ADME), drug influx, drug efflux, drug activation and inactivation, drug target alteration, DNA damage repair, cell death (in particular apoptosis) inhibition, epigenetic effects, epithelial-to-mesenchymal transition (EMT), changes in tumor environment, angiogenesis, metastasis. Sorcin participates in several of such MDR mechanisms (indicated in red, see text).

Figure 2

Upper panel. Alignment between human sorcin (hSor) and mouse sorcin (mSor). The variant residues are indicated in red. The “+” indicates residues with similar characteristics. Lower panel. The X-ray crystal structure of human sorcin in the apo form (gray) and in the calcium-bound form (blue; calcium ions are represented by yellow spheres). Upon calcium binding, sorcin activation occurs, with a transition from a closed to an open structure (see also detail of the EF3 hand), involving a movement of the long D-helix of 21°.

Figure 2

Upper panel. Alignment between human sorcin (hSor) and mouse sorcin (mSor). The variant residues are indicated in red. The “+” indicates residues with similar characteristics. Lower panel. The X-ray crystal structure of human sorcin in the apo form (gray) and in the calcium-bound form (blue; calcium ions are represented by yellow spheres). Upon calcium binding, sorcin activation occurs, with a transition from a closed to an open structure (see also detail of the EF3 hand), involving a movement of the long D-helix of 21°.

Figure 3

Ca²⁺-bound sorcin in complex with a peptide belonging to the N-terminal domain. Left: Upon calcium binding to sorcin, two hydrophobic patches are exposed to the solvent and likely mediate target binding. One patch (violet) arises from the opening of EF1, the other (blue) from EF3. The peptide belonging to the sorcin N-terminal domain is shown in yellow. Right: detail of the residues involved in the exposure of the hydrophobic surfaces upon calcium binding to sorcin, belonging to the A-helix and EF1 hand (green), and to the C-helix, D-helix, EF4 loop, and G-helix (orange and cyan). The peptide belonging to the sorcin N-terminal domain (in yellow) and the residues interacting with it are represented as sticks.

Figure 4

Sorcin inhibits Ryanodine Receptors (RyRs) and activates sarco/endoplasmic reticulum Ca²⁺⁻ATPase (SERCA) and Na⁺/Ca²⁺ exchanger (NCX), thereby increasing Ca²⁺ load of the endoplasmic reticulum (ER) and decreasing ER stress (top). When sorcin expression is low, ER Ca²⁺ load is decreased, thereby increasing ER stress (bottom).

Figure 5

The ABCB1 amplicon, located in chromosomal region 7q21, containing the sorcin(SOluble Resistance-related Calcium-binding proteIN) (SRI) gene.

Figure 6

X-ray crystal structure of sorcin in complex with doxorubicin. The chemotherapeutic drug binds close to residues of the EF5 hand, interacting with residues of sorcin G- and H-helices. The two monomers of the sorcin dimer are colored blue and orange. The doxorubicin molecule (colored in yellow) and the residues interacting with it are represented as sticks.