SJSA-1

Compound YYN-37 Induces Different Forms of Cell Death in Various Tumor Cells

The PI3K/mTOR pathway is a promising cancer therapy target, though efficacy is often limited by apoptosis resistance. Hua et al. investigated the dual PI3K/mTOR inhibitor YYN-37 and its capacity to induce context-dependent cell death, particularly the non-apoptotic process of methuosis.

YYN-37 previously showed robust anti-tumor activity in vitro and in vivo, inhibiting tumor growth in colon cancer xenografts and reducing phosphorylated AKT and p70S6K in a dose- and time-dependent manner. When tested in SJSA-1 osteosarcoma cells, strikingly differential responses emerged compared to HCT-116 colorectal cancer cells (Fig. 1A). YYN-37 induced cell rounding, shrinkage, and budding in HCT-116 cells, but pronounced cytoplasmic vacuolization without shrinkage in SJSA-1 cells. Similar vacuolization was observed in HOS, MNNG/HOS, A549, and MDA-MB-231 cells. HCT-116 and SJSA-1 were selected for further investigation.

Western blot revealed cleaved-caspase-3 induction in HCT-116 but not SJSA-1 cells (Fig. 1B, C). The apoptosis inhibitor Z-VAD-FMK reversed YYN-37's effects in HCT-116 but not SJSA-1 cells (Fig. 1D, E), confirmed by TUNEL staining showing DNA fragmentation only in HCT-116 (Fig. 1F). The autophagy inhibitor 3-MA had no effect in either cell line (Fig. 1G, H), and electron microscopy showed single-membrane vacuoles rather than autophagosomes in SJSA-1 cells. Thus, YYN-37 induces apoptosis in HCT-116 cells but triggers non-apoptotic, vacuolization-mediated cell death-potentially methuosis-in SJSA-1 cells.