Page 70 - Read Online

Genovese et al. Cancer Drug Resist 2018;1:164-80 I http://dx.doi.org/10.20517/cdr.2018.10 Page 169

Sorcin has a very high expression level in the brain, 5-10 times higher than in the heart. Sorcin is one of the
most expressed Ca binding proteins in the prefrontal cortex, in the amygdala, in the hypothalamus and in
2+
2+
many brain tumors (GeneAtlas). The extent of Sorcin expression and its ability to regulate Ca homeostasis
make Sorcin a potentially important protein in brain function and dysfunction. According to the so-called
2+
2+
“Calcium Hypothesis”, deregulation of Ca -mediated signaling, perturbed ER Ca homeostasis and ER
stress are at the basis of the abnormal accumulation and aggregation of specific proteins, which are deposited
in intracellular inclusions or extracellular aggregates during brain aging and in many neurodegenerative
diseases, as Alzheimer's disease (AD) and Parkinson’s disease (PD) . PD is characterized by progressively
[45]
distributed Lewy pathology and neurodegeneration, linked to the degeneration of dopaminergic neurons
in the substantia nigra pars compacta. Ca entry through Cav1 channels, mitochondrial oxidant stress
2+
and PD pathogenesis are strictly linked . Alterations in RyR expression and function are observed in cells
[46]
bearing familial mutations in the genes of the β-amyloid precursor protein (βAPP) and of presenilins (the
catalytic core of γ-secretase complexes that cleave the βAPP to generate amyloid β-peptides), in the brain
of transgenic AD mice models and in AD-affected human brains. RyR participates in the control of βAPP
processing and of Aβ peptide production: RyR alteration or mysfunction alters neuronal death, synaptic
function and memory and learning abilities , and its regulation by Sorcin can be important in maintaining
[47]
ER Ca load in ER and possibly decreasing ER stress and unfolded protein production in the brain. Further,
2+
Sorcin is able to directly interact as a function of Ca concentration (in vitro, in cultured cells and in
2+
human brain) with alpha-synuclein (AS) and presenilin 2 (PS2), important in PD and AD pathogenesis,
respectively [48,49] . Sorcin binds to the C-terminal part of PS2 that forms low-conductance Ca channels in
2+
2+
planar lipid bilayers , interacts with RyR in a Ca -dependent fashion, and regulates Ca homeostasis .
2+
[51]
[50]
Sequestration of Sorcin by aberrant forms of tau compromises its function, impairing calcium homeostasis
and cellular resistance by ER stress, and contributing to the progression of AD . Sorcin is overexpressed in
[52]
a PD cell model induced by 1-methyl-4-phenylpyridinium ion (MPP ) in SH-SY5Y cells , which is one of
+
[53]
the most differentially expressed proteins in PD vs. normal human substantia nigra and in PD vs. human
[54]
brain samples , and is overexpressed in AD brain samples [56-58] , in particular in sporadic AD and in AD
[55]
[59]
brains with severe cerebral amyloid angiopathy , as well as in frontal cortical tissues from postmortem
[60]
cases of frontotemporal dementia . Further, Sorcin is overexpressed in 7 different Huntington’s disease
[61]
human and mice models, where it has been associated with the unfolded protein response . Sorcin also
[62]
interacts with the ionotropic glutamate receptor NMDAR1 Ca channel, important in several cascade
2+
pathways and in synaptic plasticity, in caudate-putamen nucleus , and with annexins A7 and A11, involved
[63]
in Ca homeostasis in astrocytes .
2+
[64]
SRI OVEREXPRESSION IN MD-RESISTANT CANCERS, SORCIN ROLES IN MD RESISTANCE
Sorcin was isolated in 1981 as a soluble protein expressed in hamster lung tumor cells resistant to vincristine,
and named according to its main characteristics as soluble, resistance-related, calcium binding protein
(Sorcin) . Sorcin is overexpressed in different tumors, from many tissues, mostly with an ABCB1-dependent
[65]
MD-resistant phenotype. The SRI gene resides in the same amplicon of ABCB1, in chromosome 7q21.12, and
was identified as a resistance-related gene because often its gene is co-amplified with ABCB1 in MD-resistant
cancer cells . For two decades, Sorcin overexpression was believed to be an accidental by-product of this
[1]
genomic co-amplification process ; in the last 15 years many studies have defined Sorcin as an oncoprotein,
[66]
characterized both as a marker and a cause of MD resistance (MDR).
Sorcin is overexpressed in many human cancers, including adenocarcinoma, breast cancer, colorectal cancer,
gastric cancer, lung cancer, nasopharyngeal cancer, hepatocellular carcinoma and ovarian cancer, lymphoma,
leukemia and myeloma, and particularly in cancers with ABCB1-dependent MD-resistant phenotype [67-81] .
The level of expression of Sorcin is one of the main markers of poor outcome in embryonal tumors of central
nervous system ; Sorcin is a histological marker for malignant glioma, and is overexpressed in anaplastic
[82]
astrocytoma, glioblastoma and oligodendroglioma [83-86] .