A Small Molecule Inhibitor of Monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA) Inhibits Repair of Interstrand DNA Cross-link, Enhances DNA Double Strand Break, and Sensitizes Cancer Cells to Cisplatin

Inoue, Akira; Kikuchi, Satoru; Hishiki, Asami; Shao, Youming; Heath, Richard J.; Evison, Benjamin J.; Actis, Marcelo L.; Canman, Christine E.; Hashimoto, Hiroshi; Fujii, Naoaki

doi:10.1074/jbc.m113.520429

Cited by 74 publications

(92 citation statements)

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“…Furthermore, the combination treatment increased the percentage of necrotic cells (Annexin V À /PI þ ) and dead cells (Annexin V þ /PI þ ) compared with cisplatin treatment alone (Fig. 2F), confirming the recent findings that inhibiting PCNA function sensitizes cells to DNA damage and cell death induced by cisplatin (34,35).…”

Section: Pcna-i1 Treatment Induces Programmed Cell Death In Prostate supporting

confidence: 77%

“…However, combination treatment of PCNA-I1 and cisplatin synergistically increased gH2AX, phospho-p53, and cleaved PARP expression and the percentage of apoptotic cells compared with cisplatin treatment alone. Similar findings of improved sensitivity to cisplatin via inhibition of translesion synthesis (TLS) using a small-molecule inhibitor of PCNA that binds to the PIP-BOX have been reported (34,35). Whether PCNA-I1 improves sensitivity to cisplatin treatment through inhibition of TLS remains to be determined.…”

Section: Discussionsupporting

confidence: 52%

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Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Dillehay

Dong

2014

Molecular Cancer Therapeutics

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Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 is most potent. The purposes of this study were to further investigate the effects of targeting PCNA chromatin association on DNA damage and cytotoxicity and to evaluate the therapeutic potential of PCNA-I1 against tumors in mice. Given the important roles of tumor suppressor p53 in regulating sensitivity of tumor cells to chemotherapeutics, we performed studies in two human prostate cancer cell lines differing in p53 expression: LNCaP cells (wild-type p53) and PC-3 cells (p53-null). PCNA-I1 induced DNA damage and apoptosis in both LNCaP and PC-3 cells and enhanced DNA damage and apoptosis triggered by cisplatin. PCNA-I1 also induced autophagy in PC-3 cells. A short-term pretreatment with PCNA-I1 reduced colony formation by 50% in both cell lines. These data suggest that, unlike many other cytotoxic drugs, the effects of PCNA-I1 on tumor cells do not depend on expression of p53. Intravenous administrations of PCNA-I1 significantly retarded growth of LNCaP tumors of in nude mice without causing detectable effects on mouse body weight and hematology profiles. These data provide proof of concept that targeting PCNA chromatin association could be a novel and effective therapeutic approach for treatment of cancer. Mol Cancer Ther; 13(12); 2817-26. Ó2014 AACR.

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Section: Pcna-i1 Treatment Induces Programmed Cell Death In Prostate supporting

confidence: 77%

Section: Discussionsupporting

confidence: 52%

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Dillehay

Dong

2014

Molecular Cancer Therapeutics

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“…Proliferation in T. brucei overexpressing HsPCNA rose significantly and reached a maximum when the dose of T2AA reached 6 M and then decreased, providing further evidence that PCNA/PIP-box protein interactions had a critical role in triggering cell cycle arrest in parasites that overexpress HsPCNA ( Figure 3B). Bell-shaped dosage curves are not unusual for drugs and might occur as a result of two binding sites (Inoue et al, 2014) or other mechanisms such as colloidal formation (Owen et al, 2014). This contrasting observation indicates that T2AA selectively inhibits HsPCNA over TbPCNA.…”

Section: Specific Inhibition Of Stable Pcna/pip-box Protein Interactimentioning

confidence: 77%

“…It was intriguing to us why we see this differential effect of T2AA on human versus T. brucei PCNA. By taking a closer look at the IDCL sequence alignments between the two proteins, it was revealed that methionine (M*) is present in TbPCNA at the position of the key binding residue Q131 in HsPCNA, which forms hydrogen bonds with the phenolic group of T2AA (Inoue et al, 2014;Punchihewa et al, 2012). Q131 is critical for high binding affinity between HsPCNA and p21 by forming a hydrogen bond to Y151 of p21 (Kroker and Bruning, 2015).…”

Section: Comparison Of T2aa Binding Tomentioning

confidence: 99%

“…The PIP-box is represented by the consensus sequence (Qxxx) where = (hydrophobic residues) and = (aromatic residues) that determines how well the motif can pack into the hydrophobic pocket formed by the interdomain-connecting loop and central loop of PCNA (Bruning and Shamoo, 2004;Gulbis et al, 1996;Moldovan et al, 2007). Basic knowledge about PCNA/PIP-box interactions has translated to the pre-clinical proof-of-mechanism for the inhibitor T2AA to therapeutically target HsPCNA in cancer cells (Actis et al, 2013;Inoue et al, 2014;Punchihewa et al, 2012;Tan et al, 2012). There is a homolog of PCNA in T. brucei, TbPCNA, which is regulated through the cell cycle, and which is located at the nuclear periphery (Kaufmann et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Selective inhibition T2AA for human PCNA over PCNA homolog in Trypanosoma brucei

Haggag¹,

Nossair²,

Elaadli³

et al. 2018

AJVS

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Key words:T2 amini alcohol, Proliferating cell nuclear antigen and Trypanosoma brucei.Proliferating cell nuclear antigen (PCNA) coordinates many functions including cell cycle progression and DNA replication in eukaryotic cells. Inhibition of the PCNA protein function in Trypanosoma brucei could be a new strategy in controlling Human African Trypanosomiasis. In the present study, we explored the function of TbPCNA by deregulation the protein expression through the overexpression, and by applying the small molecule inhibition. Overexpression of human PCNA or T. brucei PCNA wildtype proteins inhibits the parasite proliferation. On the other hand, T. brucei that overexpress the HsPCNA M40A or TbPCNA M40A mutants grew normally, indicating that inhibition of PIP-box protein interaction is important for the lethal phenotype. In testing this hypothesis, we applied the small molecule inhibitor T2 amino alcohol (T2AA). Proliferation in parasites that overexpress HsPCNA resumed after T2AA treatment, but not parasites that overexpressed TbPCNA. We concluded that T2AA selectively inhibits HsPCNA not TbPCNA. This data presented here will be a prerequisite for investigating TbPCNA interacting proteins and discovering inhibitors that specifically target TbPCNA to kill the parasite.

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Structural analyses of PCNA from the fungal pathogen Candida albicans identify three regions with species‐specific conformations

et al. 2021

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An assembly of multiprotein complexes achieves chromosomal DNA replication at the replication fork. In eukaryotes, proliferating cell nuclear antigen (PCNA) plays a vital role in the assembly of multiprotein complexes at the replication fork and is essential for cell viability. PCNA from several organisms, including Saccharomyces cerevisiae, has been structurally characterised. However, the structural analyses of PCNA from fungal pathogens are limited. Recently, we have reported that PCNA from the opportunistic fungal pathogen Candida albicans complements the essential functions of ScPCNA in S. cerevisiae. Still, it only partially rescues the loss of ScPCNA when the yeast cells are under genotoxic stress. To understand this further, herein, we have determined the crystal structure of CaPCNA and compared that with the existing structures of other fungal and human PCNA. Our comparative structural and in‐solution small‐angle X‐ray scattering (SAXS) analyses reveal that CaPCNA forms a stable homotrimer, both in crystal and in solution. It displays noticeable structural alterations in the oligomerisation interface, P‐loop and hydrophobic pocket regions, suggesting its differential function in a heterologous system and avenues for developing specific therapeutics. Databases The PDB and SASBDB accession codes for CaPCNA are https://doi.org/10.2210/pdb7BUP/pdb and SASDHQ9, respectively.

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A Small Molecule Inhibitor of Monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA) Inhibits Repair of Interstrand DNA Cross-link, Enhances DNA Double Strand Break, and Sensitizes Cancer Cells to Cisplatin

Cited by 74 publications

References 50 publications

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

Selective inhibition T2AA for human PCNA over PCNA homolog in Trypanosoma brucei

Structural analyses of PCNA from the fungal pathogen Candida albicans identify three regions with species‐specific conformations

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