Not only P-glycoprotein: amplification of the ABCB1-containing chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance-related proteins

The development of drug resistance continues to be a dominant hindrance toward curative cancer treatment. Overexpression of a wide-spectrum of ATP-dependent efflux pumps, and in particular of ABCB1 (P-glycoprotein or MDR1) is a well-known resistance mechanism for a plethora of cancer chemotherapeutics including for example taxenes, anthracyclines, Vinca alkaloids, and epipodopyllotoxins, demonstrated by a large array of published papers, both in tumor cell lines and in a variety of tumors, including various solid tumors and hematological malignancies. Upon repeated or even single dose treatment of cultured tumor cells or tumors in vivo with anti-tumor agents such as paclitaxel and doxorubicin, increased ABCB1 copy number has been demonstrated, resulting from chromosomal amplification events at 7q11.2-21 locus, leading to marked P-glycoprotein overexpression, and multidrug resistance (MDR). Clearly however, additional mechanisms such as single nucleotide polymorphisms (SNPs) and epigenetic modifications have shown a role in the overexpression of ABCB1 and of other MDR efflux pumps. However, notwithstanding the design of 4 generations of ABCB1 inhibitors and the wealth of information on the biochemistry and substrate specificity of ABC transporters, translation of this vast knowledge from the bench to the bedside has proven to be unexpectedly difficult. Many studies show that upon repeated treatment schedules of cell cultures or tumors with taxenes and anthracyclines as well as other chemotherapeutic drugs, amplification, and/or overexpression of a series of genes genomically surrounding the ABCB1 locus, is observed. Consequently, altered levels of other proteins may contribute to the establishment of the MDR phenotype, and lead to poor clinical outcome. Thus, the genes contained in this ABCB1 amplicon including ABCB4, SRI, DBF4, TMEM243, and RUNDC3B are overexpressed in many cancers, and especially in MDR tumors, while TP53TG1 and DMTF1 are bona fide tumor suppressors. This review describes the role of these genes in cancer and especially in the acquisition of MDR, elucidates possible connections in transcriptional regulation (co-amplification/repression) of genes belonging to the same ABCB1 amplicon region, and delineates their novel emerging contributions to tumor biology and possible strategies to overcome cancer MDR

Roles of Sorcin in Drug Resistance in Cancer: One Protein, Many Mechanisms, for a Novel Potential Anticancer Drug Target

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

Attitudes, perceptions, and knowledge of the population on End-of-Life and Advance Treatment Declaration: an observational study in Southern Italy

In an advanced scientific and technological context, where it is now tangible the possibility of interfering indefinitely in the process of dying, it becomes necessary to disseminate knowledge about end of life that, for the great variety of areas that it invests, presents many controversial aspects. With the Law no. 219/2017, the right of self-determination and freedom of treatment of the patient is enshrined, aspects that to date still remain too little discussed. An online survey was conducted from December 2019 to February 2020, among the population residing in the provinces of Lecce and Brindisi, spread thanks to the collaboration of local authorities. A large part of the sample (82.4%, N=333) claims the right to self-determination, stating that therapeutic decisions are up to the patient who has signed his advance treatment dispositions, declared absolutely binding for 50% (N=205) of the sample. However, there is still a lack of information about how to draw up advance treatment agreements (AADs). 12.6% (N=51) of those interviewed stated that they knew nothing about it and only 32.9% (N=133) felt ready and adequately informed to make their own declarations. Another peculiar aspect is that topics such as euthanasia and assisted suicide seem to be considered at the margins of acceptability among End-of-Life instances. The results of the study show that knowledge on the subject has definitely improved over the years and that in most of the issues addressed, the population has an adequate degree of preparedness even though there is still some skepticism in dealing with issues such as assisted suicide and euthanasia. Future research could explore the possibility of identifying effective training tools and communication strategies that can be used by the widest possible segment of the population

Sorcin is an early marker of neurodegeneration, Ca2+ dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases

Dysregulation of calcium signaling is emerging as a key feature in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), and targeting this process may be therapeutically beneficial. Under this perspective, it is important to study proteins that regulate calcium homeostasis in the cell. Sorcin is one of the most expressed calcium-binding proteins in the human brain; its overexpression increases endoplasmic reticulum (ER) calcium concentration and decreases ER stress in the heart and in other cellular types. Sorcin has been hypothesized to be involved in neurodegenerative diseases, since it may counteract the increased cytosolic calcium levels associated with neurodegeneration. In the present work, we show that Sorcin expression levels are strongly increased in cellular, animal, and human models of AD, PD, and HD, vs. normal cells. Sorcin partially colocalizes with RyRs in neurons and microglia cells; functional experiments with microsomes containing high amounts of RyR2 and RyR3, respectively, show that Sorcin is able to regulate these ER calcium channels. The molecular basis of the interaction of Sorcin with RyR2 and RyR3 is demonstrated by SPR. Sorcin also interacts with other ER proteins as SERCA2 and Sigma-1 receptor in a calcium-dependent fashion. We also show that Sorcin regulates ER calcium transients: Sorcin increases the velocity of ER calcium uptake (increasing SERCA activity). The data presented here demonstrate that Sorcin may represent both a novel early marker of neurodegenerative diseases and a response to cellular stress dependent on neurodegeneration

Sorcin, a calcium binding protein involved in the multidrug resistance mechanisms in cancer cells

Sorcin is a penta-EF hand calcium binding protein, which participates in the regulation of calcium homeostasis in cells. Sorcin regulates calcium channels and exchangers located at the plasma membrane and at the endo/sarcoplasmic reticulum (ER/SR), and allows high levels of calcium in the ER to be maintained, preventing ER stress and possibly, the unfolded protein response. Sorcin is highly expressed in the heart and in the brain, and overexpressed in many cancer cells. Sorcin gene is in the same amplicon as other genes involved in the resistance to chemotherapeutics in cancer cells (multi-drug resistance, MDR) such as ABCB4 and ABCB1; its overexpression results in increased drug resistance to a number of chemotherapeutic agents, and inhibition of sorcin expression by sorcin-targeting RNA interference leads to reversal of drug resistance. Sorcin is increasingly considered a useful marker of MDR and may represent a therapeutic target for reversing tumor multidrug resistance

Molecular bases of Sorcin-dependent resistance to chemotherapeutic agents

Soluble resistance-related calcium binding protein (Sorcin) is a protein initially labelled “resistance-related”, since it is co-amplified with ABCB1 in multidrug (MD)-resistant cells. While for years Sorcin overproduction was believed to be a by-product of the co-amplification of its gene with the P-glycoprotein gene, many recent studies view Sorcin as an oncoprotein, playing an important role in MD resistance (MDR). Sorcin is one of the most highly expressed calcium-binding proteins, which is overexpressed in many human tumors and MD resistant cancers, and represents a novel MDR marker. Sorcin expression in tumors inversely correlates with patients’ response to chemotherapies and overall prognosis. Sorcin is highly expressed in MDR cell lines over their parent cells. Sorcin overexpression by gene transfection increases drug resistance to a variety of chemotherapeutic drugs in many cancer lines. On the other hand, Sorcin silencing leads to reversal of drug resistance in many cell lines. This review describes: (1) the roles of Sorcin in the cell; (2) the studies showing Sorcin overexpression in tumors and cancer cells; (3) the studies showing the effects of Sorcin overexpression and silencing; (4) the molecular effects of Sorcin overexpression; and (5) the structural and genetic bases of Sorcin-dependent MDR

Molecular bases of Sorcin-dependent resistance to chemotherapeutic agents

Soluble resistance-related calcium binding protein (Sorcin) is a protein initially labelled “resistance-related”, since it is co-amplified with ABCB1 in multidrug (MD)-resistant cells. While for years Sorcin overproduction was believed to be a by-product of the co-amplification of its gene with the P-glycoprotein gene, many recent studies view Sorcin as an oncoprotein, playing an important role in MD resistance (MDR). Sorcin is one of the most highly expressed calcium-binding proteins, which is overexpressed in many human tumors and MD resistant cancers, and represents a novel MDR marker. Sorcin expression in tumors inversely correlates with patients’ response to chemotherapies and overall prognosis. Sorcin is highly expressed in MDR cell lines over their parent cells. Sorcin overexpression by gene transfection increases drug resistance to a variety of chemotherapeutic drugs in many cancer lines. On the other hand, Sorcin silencing leads to reversal of drug resistance in many cell lines. This review describes: (1) the roles of Sorcin in the cell; (2) the studies showing Sorcin overexpression in tumors and cancer cells; (3) the studies showing the effects of Sorcin overexpression and silencing; (4) the molecular effects of Sorcin overexpression; and (5) the structural and genetic bases of Sorcin-dependent MDR