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Page 170 Genovese et al. Cancer Drug Resist 2018;1:164-80 I http://dx.doi.org/10.20517/cdr.2018.10

Figure 4. Multidrug-resistance (MDR) depends on a series of factors, including absorption, distribution, metabolism, elimination (ADME),
drug influx and efflux, drug activation/inactivation, drug target alteration, DNA damage repair, cell death inhibition, epigenetic alteration and
epithelial-to-mesenchymal transition (EMT). Sorcin contributions to the onset of a MD-resistant phenotype are indicated in red (see text)

Sorcin is an oncoprotein with multifaceted activity in both tumorigenesis and the onset of a MD-resistant
phenotype [Figure 4]. Sorcin, by loading calcium in ER and mitochondria, prevents ER stress and possibly
the unfolded protein response, and increases cell escape from apoptosis [10,11,78] : in MD-resistant tumor cells
overexpressing Sorcin, the equilibrium between cell life and death is shifted towards proliferation.

In doxorubicin-resistant leukemia cell lines, Sorcin is overexpressed with respect to the drug-sensitive parental
cell line. In leukemia patients, Sorcin expression level correlates with low-response to chemotherapies and
poor prognosis; Sorcin overexpression (with gene transfection techniques) increases MDR to doxorubicin,
vincristine, etoposide and homoharringtonine in leukemia K562 cells and in lung tumors, to doxorubicin,
vincristine, paclitaxel and 5-fluorouracil in SGC7901 cells, ovarian and breast cancer [22,69,72,74,76,87] . Conversely,
Sorcin silencing reverses MDR in many tumor cell lines, as MD-resistant leukemia and Sorcin-transfected
leukemia cells, breast cancer, HeLa, colorectal cancer and nasopharyngeal carcinoma cells [2,22,74-78,88-94] . In a
lung cancer cell line, Sorcin silencing decreases ABCB1 protein levels and ABCB1 activity, thereby decreasing
rhodamine123 efflux [Table 1].
[87]

Sorcin is also able to bind directly and with high affinity several chemotherapeutic drugs, as doxorubicin,
paclitaxel, vinblastine and cisplatin; Sorcin acts as a cytosolic drug scavenger, thereby reducing doxorubicin
nuclear uptake, and allowing an increase of drug resistance and of cell survival . Sorcin binds doxorubicin
[87]
with high affinity in a site at the EF5 hand, which is involved in Sorcin dimerization and does not bind
calcium with high affinity [Figure 5], and changes cell localization upon doxorubicin treatment, and
presumably upon drug binding .
[87]

Sorcin overexpression increases migration, invasion and metastasis in vitro, while Sorcin silencing inhibits
the epithelial-to-mesenchymal (EMT) transition in a human breast cancer cell line, possibly via E-cadherin
and VEGF expression, and reduces breast cancer metastasis . Sorcin induces migration and invasion also
[94]
in gastric cancer cells, while inhibition of Sorcin expression down-regulates the expression of markers of
invasion, migration and proliferation as MMP2, MMP9, CTSZ and p-STAT3, followed by suppression of
tumor growth and metastasis . Sorcin interacts with STAT3 and increases its phosphorylation, thereby
[95]
negatively regulating NF-κB signaling .
[96]