Title: “Water-Soluble Mn(III)-Porphyrins with High Relaxivity and Photosensitization”

Author(s): Nemeth, Tamas; Pallier, Agnes; Çelik, Çetin; garda, zoltan; Yoshizawa-Sugata, Naoko; Masai, Hisao; Tóth, Éva; Yamakoshi, Yoko

ABSTRACT: Three water-soluble Mn(III)-porphyrin complexes with cationic pyridyl side groups bearing COOH- or OH-terminated carbon chains in the meta or para positions have been synthesized as probes for both magnetic resonance imaging (MRI) and photodynamic therapy (PDT). The complexes Mn-1, Mn-2, and Mn-3 are highly water-soluble, and their relaxivities range between 10-15 mM^-1s^-1, at 20-80 MHz and 298K, 2-3 times higher than that of commercial Gd(III)-based agents. The complexes containing carboxylate (Mn-2) or alcoholic (Mn-3) side chains in para position are endowed with higher relaxivities and have also shown efficient photoinduced DNA cleavage and singlet oxygen (¹O₂) generation. Mn-3 with stronger photoinduced DNA cleavage has also revealed stabilizing and binding activities for G4 DNA, at a similar level as the known G4 binder Mn-TMPyP4. Nevertheless, the G4-binding activity of Mn-3 was non-specific. Preliminary tests evidenced photocytotoxicity of Mn-3 on HeLa cells without significant effect in the absence of light. Altogether, these results underline the potential of such water-soluble Mn(III)-porphyrins for the development of multimodal approaches combining MRI and PDT.

2024年8月14日

Zhiying You 研究員のMCMについての総説（Assembly, activation and helicase actions of MCM）がBiology誌にアクセプトされました。これは、Peter J. Gillespie博士（Cancer Research UK Chromosome Replication)が企画したReplication Licensing and MCM2-7 functionに関する特集号です。

総説のpreprintはここからダウンロードできます。

2024年3月13日

大学院生の山﨑航輔君、笹沼博之副参事研究員の論文『Homologous recombination contributes to the repair of acetaldehyde-induced DNA damages 』がCell Cycle誌(IF 4.7)への掲載が許可されました。

この論文では、アセトアルデヒドにより誘導されるDNA損傷が、相同組換え依存的修復システムで修復されることを示しました。

Abstract

Acetaldehyde, a chemical that can cause DNA damage and contribute to cancer, is prevalently present in our environment, e.g., in alcohol, tobacco, and food. Although aldehyde potentially promotes crosslinking reactions among biological substances including DNA, RNA, and proteins, it remains unclear what types of DNA damage are caused by acetaldehyde and how they are repaired. In this study, we examined the acetaldehyde sensitivity of DNA damage-deficient cells established from the human TK6 cell line. Among the mutants, mismatch repair mutants did not show hypersensitivity to acetaldehyde, while cells deficient in base and nucleotide excision repair pathways increased their sensitivity. We found a delayed repair and hypersensitivity in homologous recombination (HR)-deficient cells but not in nonhomologous end joining-deficient cells after acetaldehyde treatment. By analyzing the formation of acetaldehyde-induced RAD51 foci, which represent HR intermediates, HR-deficient cells, but not NHEJ, exhibit delayed repair of acetaldehyde-induced DNA damages, compared with wild-type. These results suggest that acetaldehyde causes complex DNA damages that require various types of repair pathways. Interestingly, mutants deficient in TDP1 and TDP2, which are involved in the removal of protein adducts from DNA ends, exhibited hypersensitivity to acetaldehyde. The acetaldehyde sensitivity of the double mutant deficient in both TDP1 and RAD54 was similar to that of each single mutant. This epistatic relationship between TDP1 and RAD54 suggests that the removal of protein-DNA adducts generated by acetaldehyde needs to be removed for efficient repair by HR. Our study would help understand the molecular mechanism of the genotoxic and mutagenic effects of acetaldehyde.

KEY WORDS: homologous recombination, acetaldehyde, DNA-protein adducts

2023年10月16日

田島陽一研究員の論文『Cell fusion upregulates PD-L1 expression for evasion from immunosurveillance 』がCancer Gene Therapy誌(IF 6.4)への掲載が許可されました。

この論文では、自発的は細胞融合が、がん細胞の増悪化を誘導するメカニズムの一端を明らかにしました。

Abstract

MSCs (mesenchymal stem cells), responsible for tissue repair, rarely undergo cell fusion with somatic cells. Here, we show that approximately 5% of bladder cancer cells (UMUC-3) fuses with bone marrow-derived MSC (BM-MSC) in co-culture and maintains high tumorigenicity. In eleven fusion cell clones that have been established, Mb-scale deletions carried by the bladder cancer cells are mostly absent in the fusion cells, but copy number gains contributed by the cancer cells have stayed. Fusion cells exhibit increased populations of mitotic cells with  3-polar spindles, indicative of genomic instability. They grow faster in vitro and exhibit higher colony formation in anchorage-independent growth assay in soft agar than the parent UMUC-3 does. Fusion cells develop tumors, after 4 weeks of time lag, as efficiently as the parent UMUC-3 does in xenograft experiments. 264 genes are identified whose expression is specifically altered in the fusion cells. Many of them are interferon-stimulated genes (ISG), but are activated in a manner independent of interferon. Among them, we show that PD-L1 is induced in fusion cells, and its knockout decreases tumorigenesis in a xenograft model. PD-L1 is induced in a manner independent of STAT1 known to regulate PD-L1 expression, but is regulated by histone modification, and is likely to inhibit phagocytosis by PD1-expressing macrophages, thus protecting cancer cells from immunological attacks. The fusion cells overexpress multiple cytokines including CCL2 that causes tumor progression by converting infiltrating macrophages to tumor-associated-macrophage (TAM). The results present mechanisms of how cell fusion promotes tumorigenesis, revealing a novel link between cell fusion and PD-L1, and underscore the efficacy of cancer immunotherapy.

2023年1月24日

堀さん、井口研究員の論文”Cdc7 kinase is required for postnatal brain development”が、Genes to Cells誌にacceptされました。

本研究は、当研究所の小野富男博士、丸山千秋博士らとの共同研究で行いました。