14-Deoxy-11,12-didehydroandrographolide induces DDIT3-dependent endoplasmic reticulum stress-mediated autophagy in T-47D breast carcinoma cells

• The mechanistic toxicology properties of 14-DDA in T-47D breast carcinoma cells were investigated.
• 14-DDA induces the formation of ER vacuoles and autophagosomes, with concurrent upregulation of LC3-II.
• It stimulates an increase in cytosolic calcium concentration and causing collapse in the mitochondrial membrane potential.
• Both DDIT3 and GADD45A, molecules implicated in ER stress pathway, were significantly upregulated.
• 4-DDA induces ER stress-mediated autophagy in T-47D cells possibly via GADD45A/p38 MAPK/DDIT3 pathway.

14-Deoxy-11,12-didehydroandrographolide (14-DDA), a major diterpenoid isolated from Andrographis paniculata (Burm.f.) Nees, is known to be cytotoxic and elicits a non-apoptotic cell death in T-47D breast carcinoma cells. In this study, the mechanistic toxicology properties of 14-DDA in T-47D cells were further investigated. 14-DDA is found to induce the formation of endoplasmic reticulum (ER) vacuoles and autophagosomes, with concurrent upregulation of LC3-II in the breast carcinoma cells. It stimulated an increase in cytosolic calcium concentration and caused a collapse in mitochondrial membrane potential in these cells. In addition, both DDIT3 and GADD45A, molecules implicated in ER stress pathway, were significantly upregulated. DDIT3 knockdown suppressed the formation of both ER vacuoles and autophagosomes, indicating that 14-DDA-induced ER stress and autophagy is dependent on this transcription factor. Collectively, it is possible that GADD45A/p38 MAPK/DDIT3 pathway is involved in the 14-DDA-induced ER-stress-mediated autophagy in T-47D cells.