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.

Exosomes and breast cancer drug resistance

“…However, BC cells can employ a variety of mechanisms to escape cell death induced by chemotherapeutic drugs. These mechanisms mainly include the efflux and inactivation of drugs 20 , activation of bypass signaling or prosurvival pathways, enhancement of DNA damage repair 21 , and induction of epithelial-mesenchymal transition (EMT) 22 and stem-like property 23 . Also, a large body of evidence demonstrated that the content of exosomes secreted by tumor cells changes in response to cellular stress induced by anticancer therapy, resulting in the transfer of drug-resistant phenotypes among tumor cells in BC [24][25][26] .…”

Mitochondria: Insights into Crucial Features to Overcome Cancer Chemoresistance

“…In addition to its role in the regulation of intracellular Ca 2+ homeostasis, as the name itself suggests, it has been found to be widely overexpressed in many cancer types, especially in chemotherapy-resistant specimens [ 235 , 236 , 237 , 238 , 239 ]. In many cases, the chemoresistant phenotype was a result of Sorcin co-amplification with mdr1 , a gene coding for an ATP-binding cassette pump considered a biomarker of MDR since its overexpression facilitates the extrusion of drugs from cells [ 240 , 241 , 242 , 243 , 244 , 245 ]. Moreover, it has been demonstrated that Sorcin overexpression is related to a poor clinical outcome in leukemia patients [ 246 , 247 ], and the combination of Sorcin silencing or depletion and chemotherapy treatment improves the effectiveness of treatment and the sensitivity to death stimuli [ 248 , 249 , 250 , 251 , 252 , 253 , 254 ].…”

Role of Calcium Homeostasis in Modulating EMT in Cancer

“…One study illustrated the role of sorcin (SOluble Resistance-related Calcium-binding ProteIN) overexpression in cancer, which modulates the co-overexpression of ABC (adenosine triphosphate-binding cassette) transporters serving as a survival mechanism by efficiently effluxing drugs out of the cells, in addition to sorcin’s ability to induce EMT [ 71 ]. Currently, sorcin is viewed as an oncogene that could be central to multidrug resistance in clinical settings and a viable target for new drug discovery [ 71 ]. Furthermore, persister cells in cancer are a common cause of treatment failure and patient relapse.…”