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Thiourea compound AW00178 sensitizes human H1299 lung carcinoma cells to TRAIL-mediated apoptosis
Byung Jun Ryu1, Mi-Kyung Hwang, Mikyung Park
1Laboratory of Chemical Genomics, Pharmacology Research Center, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu, Daejeon 305-600, Republic of Korea.
Abstract:
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in a wide variety of cancer cells. Recently, cancer cell resistance to TRAIL-mediated apoptosis has become a challenging issue in the development of TRAIL-based anti-cancer therapies. In this study, we found that 1-(5-chloro-2-methyl-phenyl)-3-[4-(5-trifluoromethyl-pyrazol-1-yl)-phenyl]-thiourea (AW00178) was able to sensitize TRAIL-resistant human lung cancer H1299 cells to TRAIL-mediated apoptosis. Treatment with AW00178, either alone or in combination with TRAIL, induced the expression of CHOP, a protein related to TRAIL sensitivity, and reduced the expression of survivin, an anti-apoptotic protein involved in TRAIL resistance. Additionally, AW00178, alone or in combination with TRAIL, induced the activation of c-Jun and inactivation of Akt. A pharmacologic inhibition study revealed that c-Jun activation and Akt inactivation were strongly related to CHOP induction and survivin down-regulation, respectively. In summary, these results suggested that AW00178 mediated sensitization to TRAIL-mediated apoptosis in H1299 cells by increasing sensitivity and decreasing resistance to TRAIL via the induction of c-Jun-dependent CHOP expression and the reduction of Akt-dependent survivin expression, respectively.
Insights
The compound AW00178 sensitizes TRAIL-resistant lung cancer cells to apoptosis. It enhances TRAIL therapy by modulating CHOP and survivin expression through c-Jun and Akt pathways.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cancer cell apoptosis.
- Cancer cell resistance to TRAIL is a significant obstacle for TRAIL-based therapies.
Purpose of the Study:
- To investigate the efficacy of 1-(5-chloro-2-methyl-phenyl)-3-[4-(5-trifluoromethyl-pyrazol-1-yl)-phenyl]-thiourea (AW00178) in overcoming TRAIL resistance in human lung cancer cells.
- To elucidate the molecular mechanisms underlying AW00178's sensitization effect.
Main Methods:
- Treatment of TRAIL-resistant H1299 lung cancer cells with AW00178 and/or TRAIL.
- Analysis of CHOP (C/EBP homologous protein) and survivin expression levels.
- Assessment of c-Jun and Akt signaling pathway activation/inactivation.
- Pharmacologic inhibition studies to confirm pathway involvement.
Main Results:
- AW00178 sensitized H1299 cells to TRAIL-mediated apoptosis.
- AW00178 induced CHOP expression and reduced survivin expression.
- AW00178 activated c-Jun and inactivated Akt.
- c-Jun activation and Akt inactivation were linked to CHOP induction and survivin downregulation, respectively.
Conclusions:
- AW00178 enhances TRAIL sensitivity by upregulating c-Jun-dependent CHOP expression.
- AW00178 reduces TRAIL resistance by downregulating Akt-dependent survivin expression.
- AW00178 represents a potential therapeutic strategy to overcome TRAIL resistance in lung cancer.
