Enhancement of Apo2L/TRAIL-mediated cytotoxicity in esophageal cancer cells by cisplatin

Wilson S. Tsai, Wen Shuz Yeow, Alex Chua, Rishindra M. Reddy, Duc M. Nguyen, David S. Schrump, Dao Nguyen

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Although expressing adequate levels of functional tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4/DR5, significant proportion of cancer cells exhibit resistance to the cytotoxic effect of this ligand. Exposure of Apo2L/TRAIL-refractory cancer cells to cytotoxic chemotherapeutic agents enhances their sensitivity to Apo2L/TRAIL cytotoxicity. This study aims to elucidate the molecular mechanism responsible for the cisplatin-mediated enhancement of Apo2L/TRAIL sensitivity in cultured esophageal cancer cells. Exposure of cancer cells to sublethal concentrations of cisplatin resulted in profound potentiation of their susceptibility to Apo2L/TRAIL cytotoxicity as indicated by 2- to > 20-fold reduction in Apo2L/TRAIL IC50 values. Significant activation of caspase-8, caspase-9, and caspase-3 was observed only in cells treated with cisplatin/Apo2L/ TRAIL combination and not in those exposed to either agent alone. More importantly, activation of these key caspases was significantly abrogated by overexpression of Bc12 or by the selective caspase-9 inhibitor. This observation strongly suggested that caspase-8 activation in cells treated with the cisplatin/Apo2L/TRAIL combination was secondary to the mitochondria-mediated amplification feedback loop and activation of the executioner caspase-3 was dependent on the recruitment of the intrinsic pathway characteristic of the type II cell. Profound combination-mediated cytotoxicity and induction of apoptosis was completely suppressed either by Bc12 overexpression or by inhibition of caspase-9 activity, which conclusively pointed to the essential role of the mitochondria-dependent death signaling cascade in this process. Cisplatin sensitizes esophageal cancer cells to Apo2L/TRAIL cytotoxicity by potentiation of the mitochondria-dependent death signaling pathway that leads to amplification of caspase activation, particularly caspase-8, by the feedback loop to efficiently induce apoptosis.

Original languageEnglish
Pages (from-to)2977-2990
Number of pages14
JournalMolecular Cancer Therapeutics
Volume5
Issue number12
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

Fingerprint

Esophageal Neoplasms
Cisplatin
Caspase 9
Caspase 8
Mitochondria
Apoptosis
Caspases
Caspase 3
TNF-Related Apoptosis-Inducing Ligand Receptors
Ligands
Neoplasms
Caspase Inhibitors
Cytotoxins
Inhibitory Concentration 50
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Enhancement of Apo2L/TRAIL-mediated cytotoxicity in esophageal cancer cells by cisplatin. / Tsai, Wilson S.; Yeow, Wen Shuz; Chua, Alex; Reddy, Rishindra M.; Nguyen, Duc M.; Schrump, David S.; Nguyen, Dao.

In: Molecular Cancer Therapeutics, Vol. 5, No. 12, 01.12.2006, p. 2977-2990.

Research output: Contribution to journalArticle

Tsai, Wilson S. ; Yeow, Wen Shuz ; Chua, Alex ; Reddy, Rishindra M. ; Nguyen, Duc M. ; Schrump, David S. ; Nguyen, Dao. / Enhancement of Apo2L/TRAIL-mediated cytotoxicity in esophageal cancer cells by cisplatin. In: Molecular Cancer Therapeutics. 2006 ; Vol. 5, No. 12. pp. 2977-2990.
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