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<p>Bacoside A (BCA), a triterpenoid saponin isolated from <i>Bacopa monnieri</i>, exhibits diverse pharmacological properties, including neuroprotective, hepatoprotective, anti-stress, anti-inflammatory, and anti-ulcer effects. In the present study, BCA demonstrates pronounced anticancer activity against K562 chronic myelogenous leukemia (CML) cells by modulating autophagy-apoptosis dynamics. BCA induces dose- and time-dependent cytotoxicity in K562 cells while sparing normal human peripheral blood mononuclear cells (hPBMCs) and Vero cells, indicating therapeutic selectivity. Mechanistically, BCA elicits a biphasic cellular response characterized by autophagy induction at 24&#xa0;h, followed by caspase-dependent apoptosis at 48&#xa0;h. Autophagy activation was confirmed by the formation of Monodansylcadaverine-positive autophagic vacuoles, upregulation of Beclin-1 and LC3-II, and increased LC3 puncta in EGFP-LC3-transfected K562 cells. Notably, BCA treatment led to persistent accumulation of p62/SQSTM1 despite functional autophagic flux. Co-immunoprecipitation analysis revealed p62/SQSTM1–LC3-II interactions, while siRNA-mediated silencing of p62/SQSTM1 attenuated LC3-II accumulation, implicating p62/SQSTM1 as a positive modulator of autophagy. Moreover, p62/SQSTM1 facilitated apoptosis progression by interacting with and activating caspase-8, thereby bridging autophagy and apoptosis. Pharmacological inhibition of autophagy using 3-methyladenine abrogated both autophagic and apoptotic responses, establishing autophagy as a prerequisite for BCA-induced cell death. BCA promoted ERK1/2 activation and concomitant suppression of mTOR pathway via dephosphorylation of mTOR and 4E-BP1. Inhibition of ERK1/2 using PD98059 reversed mTOR dephosphorylation and autophagy induction, whereas mTOR overexpression restored ERK1/2 phosphorylation to basal levels. Collectively, these findings delineate BCA as a novel autophagy-inducing agent in CML, exerting cytotoxic effects via ERK1/2-mTOR signaling and p62/SQSTM1-mediated autophagy-apoptosis crosstalk.</p>

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p62/SQSTM1 signaling nexus and orchestration of ERK and mTOR pathways are crucial for Bacoside A- induced autophagy-mediated apoptosis in chronic myelogenous leukemia

  • 期刊论文

  • 发表日期：

    2025年9月9日

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  • Sweta Kundu,
  • Suvodeep Saha,
  • Suparna Ghosh,
  • Sampriti Sarkar,
  • Atanu Kotal,
  • Avik Acharya Chowdhury

摘要

Bacoside A (BCA), a triterpenoid saponin isolated from Bacopa monnieri, exhibits diverse pharmacological properties, including neuroprotective, hepatoprotective, anti-stress, anti-inflammatory, and anti-ulcer effects. In the present study, BCA demonstrates pronounced anticancer activity against K562 chronic myelogenous leukemia (CML) cells by modulating autophagy-apoptosis dynamics. BCA induces dose- and time-dependent cytotoxicity in K562 cells while sparing normal human peripheral blood mononuclear cells (hPBMCs) and Vero cells, indicating therapeutic selectivity. Mechanistically, BCA elicits a biphasic cellular response characterized by autophagy induction at 24 h, followed by caspase-dependent apoptosis at 48 h. Autophagy activation was confirmed by the formation of Monodansylcadaverine-positive autophagic vacuoles, upregulation of Beclin-1 and LC3-II, and increased LC3 puncta in EGFP-LC3-transfected K562 cells. Notably, BCA treatment led to persistent accumulation of p62/SQSTM1 despite functional autophagic flux. Co-immunoprecipitation analysis revealed p62/SQSTM1–LC3-II interactions, while siRNA-mediated silencing of p62/SQSTM1 attenuated LC3-II accumulation, implicating p62/SQSTM1 as a positive modulator of autophagy. Moreover, p62/SQSTM1 facilitated apoptosis progression by interacting with and activating caspase-8, thereby bridging autophagy and apoptosis. Pharmacological inhibition of autophagy using 3-methyladenine abrogated both autophagic and apoptotic responses, establishing autophagy as a prerequisite for BCA-induced cell death. BCA promoted ERK1/2 activation and concomitant suppression of mTOR pathway via dephosphorylation of mTOR and 4E-BP1. Inhibition of ERK1/2 using PD98059 reversed mTOR dephosphorylation and autophagy induction, whereas mTOR overexpression restored ERK1/2 phosphorylation to basal levels. Collectively, these findings delineate BCA as a novel autophagy-inducing agent in CML, exerting cytotoxic effects via ERK1/2-mTOR signaling and p62/SQSTM1-mediated autophagy-apoptosis crosstalk.