Trichosanthin induced apoptosis in HL-60 cells via mitochondrial and endoplasmic reticulum stress signaling pathways

Abstract

Trichosanthin (TCS), a traditional Chinese medicine, exerts antitumor activities by inducing apoptosis in many different tumor cell lines. However, the mechanisms remain obscure. The present study focused on various caspase pathways that may be involved in TCS-induced apoptosis in leukemia HL-60 cells. Key caspases in both intrinsic and extrinsic pathways including caspase-8, -9 and -3 were activated upon TCS treatment. Additionally, TCS treatment induced upregulation of BiP and CHOP and also activated caspase-4, which for the first time strongly supported the involvement of endoplasmic reticulum stress pathway in TCS-induced apoptosis. Interestingly, although caspase-8 was activated, Fas/Fas ligand pathway was not involved as evidenced by a lack of induction of Fas or Fas ligand and a lack of inhibitory effect of anti-Fas blocking antibody on TCS-induced apoptosis. Instead, caspase-8 was activated in a caspase-9 and -4 dependent manner. The involvement of mitochondria was demonstrated by the reduction of mitochondrial membrane potential and release of cytochrome c and Smac besides the activation of caspase-9. Further investigation confirmed that caspase-3 was the major executioner caspase downstream to caspase-9, -4 and -8. Taken together, our results suggested that TCS-induced apoptosis in HL-60 cells was mainly mediated by mitochondrial and ER stress signaling pathways via caspase-3.

Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia

“…Overexpression of antiapoptotic Bcl-2, Bcl-X L , or Mcl-1 has been shown to affect the efficacy of Bcr-Abl TKIs (1, 2), whereas the effect of hGal9 was not diminished by Bcl-2, Bcl-X L , or Mcl-1, perhaps because hGal9 also activates a Bcl-2 family-independent pathway, which eventually activates casepae-4 and caspase-8. Considering that the activation of caspase-4 and caspase-8 is involved in ER stress-induced apoptosis (30,31), and that Noxa induction by ATF3 is crucial in the cell death induced by inhibitors for ER-associated protein degradation (22), we suggest that hGal9-induced cell death may at least partly involve ER stress.…”

Involvement of endoplasmic reticulum stress in adenosine-induced human hepatoma HepG2 cell apoptosis

“…The fact that overexpression of CHOP results in growth arrest and apoptosis has been demonstrated in a rat model (39) and in Hl-60 cells (40). translocation of cHop from the cytoplasm to the nucleus could regulate the expression of ERS-related genes (17,43).…”

The mechanisms of action of Tianhua™on antitumor activity in lung cancer cells

“…Extracts from the roots of Trichosanthes kirilowii induce apoptosis in leukemia cells and glioblastoma multiforme and prolong survival of tumor-bearing mice (Li et al, 2007;Yin et al, 2008). The relationship between apoptosis and cancer has been emphasized with an increasing body of evidence, and the induction of tumor cell apoptosis is the basis of many cancer therapies (Lee et al, 2006).…”