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

Bioorganic & medicinal chemistry letters 2024 Sep 15

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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. Copyright © 2024 Elsevier Ltd. All rights reserved.

Citation

Misaki Kabasawa, Masateru Furuta, Yuuka Ibayashi, Kaori Kanemaru, Haruki Kohatsu, Fumiyo Kuramochi, Kenji Yamatoya, Kazuya Nakata, Yoshikazu Nakamura, Shusuke Tomoshige, Kenji Ohgane, Yuuki Furuyama, Ryoko Takasawa, Susumu Kobayashi, Fumio Sugawara, Masahiko Ikekita, Kouji Kuramochi. Plakevulin A induces apoptosis and suppresses IL-6-induced STAT3 activation in HL60 cells. Bioorganic & medicinal chemistry letters. 2024 Sep 15;110:129886