Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors

Qi, Jing; Dong, Zizheng; Liu, Jianguo; Peery, Robert C.; Zhang, Shaobo; Liu, Jing Yuan; Zhang, Jian-Ting

doi:10.1158/0008-5472.can-15-1874

Cited by 56 publications

(101 citation statements)

References 51 publications

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“…Cytotoxicity was determined using MTT and colony formation assays as previously described (2,16). MTT assay was used to determine cytotoxicity of anticancer drugs.…”

Section: Methodsmentioning

confidence: 99%

14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

Chen

Dong

et al. 2017

Molecular Cancer Research

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14-3-3σ has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3σ contributes to these resistances via inhibiting apoptosis and arresting cells in G2/M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3σ causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2/M phase following DNA-damaging treatments. We showed that 14-3-3σ contributed to ionizing radiation (IR) resistance by arresting cancer cells in G2/M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSBs). The increased NHEJ repair activity was due to 14-3-3σ-mediated up-regulation of Poly(ADP-ribose) polymerase 1 (PARP1) expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the other hand, the increased G2/M arrest following IR was due to 14-3-3σ-induced Chk2 expression. Implications These findings reveal an important molecular basis of 14-3-3σ function in cancer cell resistance to chemo/radiation therapy and in poor prognosis of human cancers.

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“…Cytotoxicity was determined using MTT and colony formation assays as previously described (2,16). MTT assay was used to determine cytotoxicity of anticancer drugs.…”

Section: Methodsmentioning

confidence: 99%

14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

Chen

Dong

et al. 2017

Molecular Cancer Research

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“…These INC [16][17][18][19][20][21][22] derivatives also showed saturation and fitted well with the one binding site model ( Figure S1G-I). Both INC [15][16][17][18][19][20][21][22] and INC [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] , which have longer sequences than INC [16][17][18][19][20][21][22] , showed moderate binding affinities (K d = 248 and 160 nmol L −1 , respectively), as shown in Table 2.…”

Section: Synthesis and Binding Affinity Assessment Of Inc 16-22 Dermentioning

confidence: 99%

“…Although several of these small molecules have shown significant anticancer effects through survivin degradation in vitro and in vivo, there have been no reports regarding this type of agent proceeding to clinical studies. [27][28][29][30] For cancer-specific diagnosis, we have recently reported several radioiodinated small molecules targeting the survivin dimer site as nuclear medicine imaging agents; however, these agents have limitations, such as the lack of in vivo pharmacokinetics and specificity. 31,32 Survivin contains a single N-terminal baculovirus IAP repeat domain linked to a long C-terminal α-helix coiled domain.…”

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confidence: 99%

Discovery of inner centromere protein‐derived small peptides for cancer imaging and treatment targeting survivin

et al. 2020

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Survivin belongs to the inhibitor of apoptosis protein family, which is consistently overexpressed in most cancer cells but rarely expressed in normal adult tissues. Therefore, the detection and inhibition of survivin are regarded as attractive strategies for cancer-specific treatment. In this study, we designed and synthesized 7-19 residues of inner centromere protein (INCENP)-derived small peptides (INC peptides) as novel survivin-targeting agents. The INC peptides showed binding affinity for the human survivin protein (K d = 91.4-255 nmol L −1 ); INC 16-22 , which contains residues 16-22 of INCENP, showed the highest affinity (91.4 nmol L −1 ). Confocal fluorescence imaging showed consistent colocalization of FITC-INC 16-22 and survivin in cell lines. Nona-arginine-linked INC 16-22 (r9-INC 16-22 ) rendered INC 16-22 cells penetrable and strongly inhibited cell growth of MIA PaCa-2 cells (52% inhibition at 1.0 µmol L −1 ) and MDA-MB-231 cells (60% inhibition at 10 µmol L −1 ) as determined by MTT assays. The exposure of MIA PaCa-2 cells to 40 µmol L −1 r9-INC 16-22 apparently reduced the intracellular protein expression levels of survivin. However, cleaved caspase-3 was significantly increased in cells treated with r9-INC 16-22 , even at 10 µmol L −1 , compared to untreated cells. Flow cytometry revealed that r9-INC 16-22 strongly induced apoptosis in MIA PaCa-2 cells. These results indicate that the cytotoxic effects of r9-INC 16-22 could be mediated mainly through the disruption of survivin-dependent antiapoptotic functions and partly because of the direct degradation of the survivin protein. Our findings suggest that INC peptides can act as useful scaffolds for novel cancer imaging and anticancer agents. K E Y W O R D S anticancer, apoptosis, cancer imaging, peptide, survivin 1 | INTRODUC TI ON Survivin, the smallest protein (16.5 kDa) among the inhibitor of apoptosis protein (IAP) family, is one of the most cancer-specific proteins 1,2 ; it is highly overexpressed in most cancers, but barely detected in the majority of normal cells. 3-6 Survivin is involved in at least 2 essential cellular processes, inhibition of apoptosis and regulation of the cell cycle. 5 Furthermore, it participates in another antiapoptotic effect by S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Fuchigami T, Ishikawa N, Nozaki I, et al. Discovery of inner centromere protein-derived small peptides for cancer imaging and treatment targeting survivin.

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“…The role of Survivin in cancer has recently been reviewed extensively 144– 147 . Therapeutic targeting of Survivin has been mostly confined to non-small-molecule strategies 148, 149 and repression of protein translation 150– 152 (reviewed in 153), and only recently have small-molecule inhibitors been reported 154, 155 .…”

Section: Inhibitor Of Apoptosis and Cancermentioning

confidence: 99%

Inducing death in tumor cells: roles of the inhibitor of apoptosis proteins

et al. 2017

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The heterogeneous group of diseases collectively termed cancer results not just from aberrant cellular proliferation but also from a lack of accompanying homeostatic cell death. Indeed, cancer cells regularly acquire resistance to programmed cell death, or apoptosis, which not only supports cancer progression but also leads to resistance to therapeutic agents. Thus, various approaches have been undertaken in order to induce apoptosis in tumor cells for therapeutic purposes. Here, we will focus our discussion on agents that directly affect the apoptotic machinery itself rather than on drugs that induce apoptosis in tumor cells indirectly, such as by DNA damage or kinase dependency inhibition. As the roles of the Bcl-2 family have been extensively studied and reviewed recently, we will focus in this review specifically on the inhibitor of apoptosis protein (IAP) family. IAPs are a disparate group of proteins that all contain a baculovirus IAP repeat domain, which is important for the inhibition of apoptosis in some, but not all, family members. We describe each of the family members with respect to their structural and functional similarities and differences and their respective roles in cancer. Finally, we also review the current state of IAPs as targets for anti-cancer therapeutics and discuss the current clinical state of IAP antagonists.

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Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors

Cited by 56 publications

References 51 publications

14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

Discovery of inner centromere protein‐derived small peptides for cancer imaging and treatment targeting survivin

Inducing death in tumor cells: roles of the inhibitor of apoptosis proteins

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