Abstract
Sorcin is a calcium binding protein that plays an important role in multidrug resistance (MDR) in tumors, since its expression confers resistance to doxorubicin and to other chemotherapeutic drugs. In this study, we show that Sorcin is able to bind doxorubicin, vincristine, paclitaxel and cisplatin directly and with high affinity. The high affinity binding of doxorubicin to sorcin has been demonstrated with different techniques, that is, surface plasmon resonance, fluorescence titration and X-ray diffraction. Although the X-ray structure of sorcin in complex with doxorubicin has been solved at low resolution, it allows the identification of one of the two doxorubicin binding sites, placed at the interface between the EF5 loop the G helix and the EF4 loop. We show that Sorcin cellular localization changes upon doxorubicin treatment, an indication that the protein responds to doxorubicin and it presumably binds the drug also inside the cell, soon after drug entrance. We also demonstrate that Sorcin is able to limit the toxic effects of the chemotherapeutic agent in the cell. In addition, Sorcin silencing increases cell death upon treatment with doxorubicin, increases the accumulation of doxorubicin in cell nucleus, decreases the expression of MDR1 and doxorubicin efflux via MDR1.
Highlights
The development of drug resistance is the leading cause of chemotherapy failure in cancer treatment
The fitting of fluorescence titrations for both Sorcin and SCBD are compatible with 2 doxorubicin binding sites (Figure 1, Supplementary Figure S2), with affinity constants in the same order of magnitude with respect to those measured by surface plasmon resonance (SPR) experiments, that is, 1.4 ± 1 and 734 ± 396 nM for SCBD and 0.9 ± 0.5 and 511 ± 140 nM for Sorcin in the presence of EDTA (1.2 and 360 nM; 0.9 and 318 nM for Sorcin, in the presence of 1 and 5 mM magnesium, respectively): doxorubicin binding occurs at the C-terminal calcium-binding domain, since SCBD retains the binding sites
The high level of expression of Sorcin in many tumors, especially the multidrug resistance (MDR) ones, the inverse correlation of Sorcin expression with patients’ response to chemotherapies and overall prognosis, and reversal of drug resistance upon Sorcin expression by RNA interference have recently struck the attention of many scientists
Summary
The development of drug resistance is the leading cause of chemotherapy failure in cancer treatment. Cancer cells can adopt several strategies to evade death induced by chemotherapeutic agents These include changes in apoptotic pathways, increased DNA damage repair, drug inactivation, alteration of drug targets and increased expression of ABC transporters, able to pump xenobiotics (such as toxins or drugs) out of cells.[1] Many cancer cells express large amounts of MDR1 (ABCB1, or P-glycoprotein 1), which confers them MDR.[2,3,4]. Recent data indicate that Sorcin participates in several processes that might contribute to MDR in human cancers, such as drug efflux regulation, apoptosis modulation and epithelial-to-mesenchymal transition (EMT) control.[8,9] Conflicting results are in literature on the effect of Sorcin overexpression and silencing on MDR1 expression and activity.[10,11,12,13] A complete understanding of the mechanisms and pathways by which Sorcin contributes to the MDR phenotype of tumor cells and an assessment of the overall diagnostic and therapeutic potential of sorcin in MDR are still missing
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