Nagaraj Nagathihalli
Last active: 12/19/2014

Hypoxia inhibits TRAIL-induced tumor cell apoptosis: involvement of lysosomal cathepsins.

Nagaraj NS, Vigneswaran N, Zacharias W
Apoptosis. 2007 12 (1): 125-39

PMID: 17136492 · PMCID: PMC5774619 · DOI:10.1007/s10495-006-0490-1

Tumor hypoxia interferes with the efficacy of chemotherapy, radiotherapy, and tumor necrosis factor-alpha. TRAIL (tumor necrosis factor-related apoptosis inducing ligand) is a potent apoptosis inducer that limits tumor growth without damaging normal cells and tissues in vivo. We present evidence for a central role of lysosomal cathepsins in hypoxia and/or TRAIL-induced cell death in oral squamous cell carcinoma (OSCC) cells. Hypoxia or TRAIL-induced activation of cathepsins (B, D and L), caspases (-3 and -9), Bid cleavage, release of Bax and cytochrome c, and DNA fragmentation were blocked independently by zVAD-fmk, CA074Me or pepstatin A, consistent with the involvement of lysosomal cathepsin B and D in cell death. Lysosome stability and mitochondrial membrane potential were reduced in hypoxia and TRAIL-induced apoptosis. However, TRAIL treatment under hypoxic condition resulted in diminished apoptosis rates compared to treatment under normoxia. This inhibitory effect of hypoxia on TRAIL-induced apoptosis may be based on preventing Bax activation and thus protecting mitochondria stability. Our data show that TRAIL or hypoxia independently triggered activation of cathepsin B and D leading to apoptosis through Bid and Bax, and suggest that hypoxic tissue regions provide a selective environment for highly apoptosis-resistant clonal cells. Molecular therapy approaches based on cathepsin inhibitors need to address this novel tumor-preventing function of cathepsins in OSCC.

MeSH Terms (11)

Apoptosis Biomarkers Cathepsins Cell Line, Tumor Cell Nucleus Humans Hypoxia Lysosomes Models, Biological Recombinant Proteins TNF-Related Apoptosis-Inducing Ligand

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