Overexpression and Mislocalization of the Chromosomal Segregation Protein Separase in Multiple Human Cancers

Meyer, René; Fofanov, Viacheslav Y.; Panigrahi, Anil K.; Merchant, Fatima A.; Zhang, Nenggang; Pati, Debananda

doi:10.1158/1078-0432.ccr-08-2454

Cited by 80 publications

(88 citation statements)

References 46 publications

(63 reference statements)

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“…4 Immunoblotting: Preparation of protein samples and Western blot was performed as described previously. 17,18 …”

Section: Methodsmentioning

confidence: 99%

“…HTS is an alternate approach that can be used to find potential separase inhibitors. Separase is an ideal drug target, and pharmacologic inhibition of separase enzyme is a novel strategy to treat separase-overexpressed aneuploid tumors because (1) although homozygous deletion of separase is embryonically lethal, mice with separase haploinsufficiency live a normal life with no disease phenotype compared to the wild-type animal, 29 indicating that a reduction in separase level has no adverse effect on an organism's well-being; (2) separase, a promoter of aneuploidy, is a highly specific protease that is overexpressed in a large percentage (>60%) of human breast tumors, 5 as well as in prostate tumors and osteosarcoma, 4 suggesting that attenuation of separase level pharmacologically in human cancers may kill separase-addicted aneuploid cells; and (3) separase is not only overexpressed but also constitutively mislocalized to the nucleus of the human tumors, 4 providing an opportunity to target the nuclear bound separase. Therefore, titrating down separase level therapeutically may not only inhibit tumor cell proliferation, but also effectively reverse the aneuploid phenotype in separase-overexpressed tumor cells while sparing the normal cells.…”

Section: Sepin-1 Inhibits the Growth Of Human Tumor Xenografts In Micementioning

confidence: 99%

“…3 Recent studies indicate that separase is overexpressed and mislocalized in a number of human tumors, including breast, prostate, and osteosarcoma. 4,5 Separase protein is significantly overexpressed in more than 60% of human breast tumors compared to the matched normal breast tissue. 5 In addition, the conditional overexpression of separase in mammary epithelial cells and in the mammary glands of transgenic mice is sufficient to induce precocious separation of sister chromatids, aneuploidy, and tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

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Identification and Characterization of Separase Inhibitors (Sepins) for Cancer Therapy

Zhang

Scorsone

et al. 2014

SLAS Discovery

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Separase is an endopeptidase that cleaves cohesin subunit Rad21, facilitating the repair of DNA damage during interphase and the resolution of sister chromatid cohesion at anaphase. Separase activity is negatively regulated by securin and Cdk1-cyclin B in vivo. Separase overexpression is reported in a broad range of human tumors, and its overexpression in mouse models results in tumorigenesis. To elucidate further the mechanism of separase function and to test if inhibition of overexpressed separase can be used as a strategy to inhibit tumor-cell proliferation, small-molecule inhibitors of separase enzyme are essential. Here, we report a high-throughput screening for separase inhibitors (Sepins). We developed a fluorogenic separase assay using rhodamine 110-conjugated Rad21 peptide as substrate and screened a small-molecule compound library. We identified a noncompetitive inhibitor of separase called Sepin-1 that inhibits separase enzymatic activity with a half maximal inhibitory concentration (IC 50 ) of 14.8 µM. Sepin-1 can inhibit the growth of human cancer cell lines and breast cancer xenograft tumors in mice by inhibiting cell proliferation and inducing apoptosis. The sensitivity to Sepin-1 in most cases is positively correlated to the level of separase in both cancer cell lines and tumors.

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“…4 Immunoblotting: Preparation of protein samples and Western blot was performed as described previously. 17,18 …”

Section: Methodsmentioning

confidence: 99%

Section: Sepin-1 Inhibits the Growth Of Human Tumor Xenografts In Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification and Characterization of Separase Inhibitors (Sepins) for Cancer Therapy

Zhang

Scorsone

et al. 2014

SLAS Discovery

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“…For instance, separase overexpression occurs in several cancers and correlates positively with tumor grade and negatively with survival. 53 Plk1 upregulation is so widespread in malignancies that it has been termed a 'general feature of human cancer.' 54 Although ORC1 and MCM5 display aberrant expression in certain transformed cells, 55 MCM5 is consistently upregulated in cancers and is considered a biomarker.…”

Section: Excess Baggage: How Cancer Cells Acquire Extra Centrosomesmentioning

confidence: 99%

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

2012

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Nearly a century ago, cell biologists postulated that the chromosomal aberrations blighting cancer cells might be caused by a mysterious organelle-the centrosome-that had only just been discovered. For years, however, this enigmatic structure was neglected in oncologic investigations and has only recently reemerged as a key suspect in tumorigenesis. A majority of cancer cells, unlike healthy cells, possess an amplified centrosome complement, which they manage to coalesce neatly at two spindle poles during mitosis. This clustering mechanism permits the cell to form a pseudo-bipolar mitotic spindle for segregation of sister chromatids. On rare occasions this mechanism fails, resulting in declustered centrosomes and the assembly of a multipolar spindle. Spindle multipolarity consigns the cell to an almost certain fate of mitotic arrest or death. The catastrophic nature of multipolarity has attracted efforts to develop drugs that can induce declustering in cancer cells. Such chemotherapeutics would theoretically spare healthy cells, whose normal centrosome complement should preclude multipolar spindle formation. In search of the 'Holy Grail' of nontoxic, cancer cell-selective, and superiorly efficacious chemotherapy, research is underway to elucidate the underpinnings of centrosome clustering mechanisms. Here, we detail the progress made towards that end, highlighting seminal work and suggesting directions for future research, aimed at demystifying this riddling cellular tactic and exploiting it for chemotherapeutic purposes. We also propose a model to highlight the integral role of microtubule dynamicity and the delicate balance of forces on which cancer cells rely for effective centrosome clustering. Finally, we provide insights regarding how perturbation of this balance may pave an inroad for inducing lethal centrosome dispersal and death selectively in cancer cells.

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“…The overexpression of WAPL correlates with the progression of cervical cancer malignancy (Table 1), and cells overexpressing WAPL develop tumors after injection into nude mice [Oikawa et al, 2004]. Separase is found to be significantly overexpressed in human breast cancer [Zhang et al, 2008b], osteosarcoma and prostate cancer (Table 1) [Meyer et al, 2009]. Its induction leads to premature separation of chromatids, lagging chromosomes with specific chromosome aneuploidies [Zhang, et al, 2008b].…”

Section: Cohesin and Cancermentioning

confidence: 99%

The expanding universe of cohesin functions: a new genome stability caretaker involved in human disease and cancer

2010

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Cohesin is responsible for sister chromatid cohesion, ensuring the correct chromosome segregation. Beyond this role, cohesin and regulatory cohesin genes seem to play a role in preserving genome stability and gene transcription regulation. DNA damage is thought to be a major culprit for many human diseases, including cancer. Our present knowledge of the molecular basis underlying genome instability is extremely limited. Mutations in cohesin genes cause human diseases such as the Cornelia de Lange syndrome and the Roberts syndrome/SC phocomelia, and all the cell lines derived from affected patients show genome instability.Cohesin mutations have also been identified in colorectal cancer. Here, we will discuss the human disorders caused by the alterations of cohesin function, with emphasis on the emerging role of cohesin as a genome stability caretaker. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 OVERVIEW OF COHESIN FUNCTIONS Canonical role of cohesinThe discovery of the cohesin complex has led to a breakthrough in clarifying the "cohesive force" in play during mitosis in holding the sister chromatids together and ensuring correct chromosome segregation. Cohesin is composed of four subunits, a pair of SMC proteins, SMC1A (MIM# 300040) and SMC3 (MIM# 606062), which are members of the Structural Maintenance of Chromosome family, and two non-SMC proteins, RAD21/Scc1 (MIM# 606462) and STAG/Scc3/Sa (Table 1) [Michaelis et al., 1997]. In vertebrates, there are two closely related Scc3 homologs, called STAG1 (MIM# 604358) and STAG2 (MIM# 604359) [Losada et al., 2000;Sumara et al., 2000]. In addition, a meiotic isoform is also present, named STAG3 (MIM# 608489) [Prieto et al., 2001]. SMC proteins are characterized by a globular hinge domain flanked by two α-helical domains ( Figure 1A) which fold back on themselves at the hinge, forming a long antiparallel α-helical coiled coil arm that brings the N and C termini together.The N-terminal contains the Walker A box (or P-loop) which binds ATP. The C-terminal holds the Walker B, binding to DNA. SMC1A and SMC3 dimerize at the hinge domains, forming a Vshaped structure through hydrophobic interactions. Basically, the cohesin complex acts as a tripartite ring in which SMC1A and SMC3 are connected by their hinge domains on one side, and RAD21 closes the ring by connecting the SMC1A and SMC3 head domains on the other side [Anderson et al., 2002;Haering et al., 2002] (Figure 2). The cohesin ring shape supports the model where interaction between cohesin and DNA is topological, the so-called "ring" or "embrace" model. According to this model, cohesin topologically encircles sister chromatids.The cohesin opens at the head domain followed by the sister chromatid entering the ring and 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 ...

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Overexpression and Mislocalization of the Chromosomal Segregation Protein Separase in Multiple Human Cancers

Cited by 80 publications

References 46 publications

Identification and Characterization of Separase Inhibitors (Sepins) for Cancer Therapy

Identification and Characterization of Separase Inhibitors (Sepins) for Cancer Therapy

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

The expanding universe of cohesin functions: a new genome stability caretaker involved in human disease and cancer

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