Plakevulin A induces apoptosis and suppresses IL-6-induced STAT3 activation in HL60 cells

  • Bioorg Med Chem Lett. 2024 Sep 15:110:129886. doi: 10.1016/j.bmcl.2024.129886.
Misaki Kabasawa  1 ,  Masateru Furuta  1 ,  Yuuka Ibayashi  1 ,  Kaori Kanemaru  1 ,  Haruki Kohatsu  1 ,  Fumiyo Kuramochi  2 ,  Kenji Yamatoya  3 ,  Kazuya Nakata  4 ,  Yoshikazu Nakamura  1 ,  Shusuke Tomoshige  5 ,  Kenji Ohgane  6 ,  Yuuki Furuyama  1 ,  Ryoko Takasawa  2 ,  Susumu Kobayashi  2 ,  Fumio Sugawara  1 ,  Masahiko Ikekita  1 ,  Kouji Kuramochi  7
Affiliations
  • 1. Department of Applied Biological Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan.
  • 2. Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba, 278-8510, Japan.
  • 3. Department of Applied Biological Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan; Laboratory of Genomic Function Engineering, Department of Life Sciences, School of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ward, Kawasaki 214-8571, Kanagawa, Japan.
  • 4. Department of Applied Biological Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan; Graduate School of Bio-Applications and Systems Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakacho, Koganei, Tokyo, 184-0012, Japan.
  • 5. Department of Applied Biological Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan; Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan.
  • 6. Department of Applied Biological Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan; Department of Chemistry, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
  • 7. Department of Applied Biological Science, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan. Electronic address: [email protected].
PMID: 38996938 DOI: 10.1016/j.bmcl.2024.129886
Abstract

(+)-Plakevulin A (1), an oxylipin isolated from an Okinawan Sponge Plakortis sp. inhibits enzymatic inhibition of DNA polymerases (pols) α and δ and exhibits cytotoxicity against murine leukemia (L1210) and human cervix carcinoma (KB) cell lines. However, the half-maximal inhibitory concentration (IC50) value for cytotoxicity significantly differed from those observed for the enzymatic inhibition of pols α and β, indicating the presence of target protein(s) Other than pols. This study demonstrated cytotoxicity against human promyelocytic leukemia (HL60), human cervix epithelioid carcinoma (HeLa), mouse calvaria-derived pre-osteoblast (MC3T3-E1), and human normal lung fibroblast (MRC-5) cell lines. This compound had selectivity to Cancer cells over normal ones. Among these cell lines, HL60 exhibited the highest sensitivity to (+)-plakevulin A. (+)-Plakevulin A induced DNA fragmentation and Caspase-3 activation in HL60 cells, indicating its role in Apoptosis induction. Additionally, hydroxysteroid 17-β dehydrogenase 4 (HSD17B4) was isolated from the HL60 lysate as one of its binding proteins through pull-down experiments using its biotinylated derivative and neutravidin-coated beads. Moreover, (+)-plakevulin A suppressed the activation of interleukin 6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3). Because the knockdown or inhibition of STAT3 induces Apoptosis and HSD17B4 regulates STAT3 activation, (+)-plakevulin A may induce Apoptosis in HL60 cell lines by suppressing STAT3 activation, potentially by binding to HSD17B4. The present findings provide valuable information for the mechanism of its action.

Keywords
Apoptosis; HSD17B4; Oxylipin; Plakevulin A; STAT3.
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