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Page 172 Genovese et al. Cancer Drug Resist 2018;1:164-80 I http://dx.doi.org/10.20517/cdr.2018.10

In the mitochondrion, Sorcin interacts with TRAP1, a mitochondrial chaperone with antioxidant and anti-
apoptotic protein, upregulated in several human tumors. TRAP1 modulates apoptosis by exerting a quality
control on the short (19-kDa) mitochondrial Sorcin isoform. TRAP1 silencing in colorectal carcinoma
cells decreases mitochondrial Sorcin expression, and Sorcin silencing increases TRAP1 degradation, while
overexpression of a TRAP1 mutant localized in the ER increases the expression of mitochondrial Sorcin
and protects from paclitaxel-dependent apoptosis . Sorcin overexpression increases ER and mitochondrial
[11]
calcium levels, while Sorcin silencing activates caspase-3, caspase-12 and GRP78/BiP, increases mitotic
defects, blocks cell cycle progression in G2/M, increases the number of rounded polynucleated cells and
induces apoptosis and cell death [10,22,78] . Sorcin overexpression in leukemia cells increases expression of Bcl-2
and decreases Bax levels .
[22]
Sorcin is an interesting oncoprotein and MDR marker, expressed in many cancer cell types, and whose
overexpression results in the MDR phenotype. Sorcin has an important role in calcium homeostasis, and
is able to interact/regulate several targets and to contribute to the onset of a MD-resistant phenotype in
different ways.

Sorcin has no enzymatic activity, and targeting its activity may prove difficult. The modulation of Sorcin
expression and activity for overcoming tumorigenesis, cancer-related EMT and MDR is a possible target:
small molecules as dihydromyricetin have been used to target Sorcin, and administration of extracts from
plants as Tegillarca granosa extract Haishengsu is another strategy used [76,99-101] . Sorcin-specific miR-1 or
antagomiR-1 are possibly the most specific ways to target Sorcin , together with approaches of Sorcin
[36]
silencing or the use of Crispr-Cas9.

THE SRI GENE RESIDES IN THE ABCB1 AMPLICON: GENE COAMPLIFICATION AND PROTEIN
COEXPRESSION IN MDR TUMORS
Sorcin was identified as “resistance-related”, because it’s encoded by a gene co-amplified with ABCB1, i.e.,
the most important broad substrate specificity ATP-dependent efflux pump, able to pump xenobiotics (such
as toxins or drugs) out of cells .
[65]
The human ABCB1 gene, in the chromosomal region 7q21.1 , confers MDR when overexpressed or
[102]
amplified [102-106] ; increased ABCB1 expression upon treatment with chemotherapeutic drug has been largely
reported in the last thirty years [107-115] .

In many types of cancers, amplification of the chromosome 7q21 region containing genes of ABCB1
and Sorcin, has been reported in MD-resistant cell lines as neuroblastoma [116] , lung cancer cells
[117]
and leukemia cells [118] . Often, genomic instability and chromosomal rearrangements result in genomic
amplification, yielding an increase in the ABCB1 gene copy number and transactivation of ABCB1
overexpression [119-124] .

Several genes surrounding ABCB1 have recently been identified as contributors to the MD-resistant
phenotype when overexpressed or amplified together with ABCB1 or suppressed in resistance-induced
cancer cell lines. Many studies describe a genomic amplification of chromosome 7q21.12 region, where
ABCB1 and other MDR-related genes reside [Figure 6], in MD-resistant tumors; the MD-resistant phenotype
depends at least in part on the amplification and/or overexpression of these genes [1,66,106,116-118,125-136] . The
ABCB1 amplicon in the chromosomal region 7q21.12 is formed by the SRI, ADAM22, DBF4, SLC25A40,
RUNDC3B (RPIP9), ABCB1, ABCB4, CROT, TP53TG1 lncRNA, TMEM243 (MGC4175) and DMTF1
(DMP1) genes [Figure 6] , that have been associated with tumorigenesis and MDR; DBF4 and Sorcin,
[137]
among these genes, are possibly the most important contributors to the MD-resistant phenotype, together