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Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-kappaB activation in gastric
1Department of Gastroenterology, Rui-jin Hospital, Shanghai, Peoples Republic of China.
Abstract:
Triptolide, a major component in the extract of Chinese herbal plant Tripterygium wilfordii Hook f (TWHf), has potential anti-neoplastic effect. In the present study we investigated the potential therapeutic effects and mechanisms of triptolide against human gastric cancer cells. Four gastric cancer cell lines with different p53 status, AGS and MKN-45 (wild type p53); MKN-28 and SGC-7901 (mutant p53) were observed as to cell growth inhibition and induction of apoptosis in response to triptolide treatment. We showed that triptolide inhibited cell growth, induced apoptosis and suppressed NK-kappaB and AP-1 transactivation in AGS cells with wild-type p53. Triptolide induced apoptosis by stimulating the expressions of p53, p21(waf1/cip1), bax protein, and increased the activity of caspases. In addition, it caused cell cycle arrest in the G(0)/G(1) phase. To examine the role of p53 in these functions, we showed that suppression of p53 level with antisense oligonucleotide abrogated triptolide-induced apoptosis and over-expression of dominant negative p53 abolished the inhibitory effect on NF-kappaB activation. Furthermore, we demonstrated that triptolide had differential effects on gastric cancer cells with different p53 status. We showed that triptolide also inhibited cell growth and induced apoptosis in MKN-45 with wild-type p53, whereas it had no significant growth-inhibition and apoptosis induction effects on the MKN-28 and SGC-7901 cells with mutant p53. Our data suggest that triptolide exhibits anti-tumor and anti-inflammatory effects by inhibiting cell proliferation, inducing apoptosis and inhibiting NF-kappaB and AP-1 transcriptional activity. However, a functional p53 is required for these proapoptotic, anti-inflammatory and anti-tumor effects.
Insights
Triptolide, derived from Tripterygium wilfordii Hook f, inhibits gastric cancer cell growth and induces apoptosis. Its anti-tumor effects are dependent on a functional p53 protein, highlighting a key mechanism for potential cancer therapies.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Triptolide, a compound from Tripterygium wilfordii Hook f (TWHf), shows promise as an anti-neoplastic agent.
- Gastric cancer remains a significant health concern, necessitating novel therapeutic strategies.
- The role of p53 in cancer cell response to natural compounds is an area of active research.
Purpose of the Study:
- To investigate the therapeutic potential and underlying mechanisms of triptolide against human gastric cancer cells.
- To determine the influence of p53 status on triptolide's efficacy in gastric cancer.
- To elucidate triptolide's effects on cell proliferation, apoptosis, and key signaling pathways.
Main Methods:
- Utilized four human gastric cancer cell lines with varying p53 statuses (wild-type and mutant).
- Assessed triptolide's impact on cell growth inhibition and apoptosis induction.
- Investigated effects on NF-kappaB and AP-1 transactivation, p53, p21(waf1/cip1), and bax protein expression, caspase activity, and cell cycle progression.
- Employed antisense oligonucleotide and dominant-negative p53 to examine p53's role.
Main Results:
- Triptolide inhibited cell growth and induced apoptosis in gastric cancer cells with wild-type p53 (AGS, MKN-45).
- Triptolide suppressed NF-kappaB and AP-1 transactivation, upregulated p53, p21(waf1/cip1), and bax, increased caspase activity, and caused G(0)/G(1) cell cycle arrest.
- Apoptosis induction and NF-kappaB inhibition by triptolide were abrogated upon p53 suppression, confirming p53's essential role.
- Triptolide showed limited efficacy in gastric cancer cells with mutant p53 (MKN-28, SGC-7901).
Conclusions:
- Triptolide exhibits anti-tumor and anti-inflammatory effects in gastric cancer cells by inhibiting proliferation and inducing apoptosis.
- A functional p53 protein is crucial for mediating triptolide's pro-apoptotic, anti-inflammatory, and anti-tumor activities.
- Triptolide's differential efficacy based on p53 status suggests its potential as a targeted therapy for gastric cancers with functional p53.