Related Experiment Videos
p53-independent apoptosis induced by paclitaxel through an indirect mechanism
J S Lanni1, S W Lowe, E J Licitra
1Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract:
The efficacy of chemotherapeutic agents may be determined by a number of different factors, including the genotype of the tumor cell. The p53 tumor suppressor gene frequently is mutated in human tumors, and this may contribute to chemotherapeutic resistance. We tested the requirement for wild-type p53 in the response of tumor cells to treatment with paclitaxel (trade name Taxol), an antineoplastic agent that stabilizes cellular microtubules. Although paclitaxel is broadly effective against human tumor xenografts in mice, including some known to carry p53 mutations, we found that p53-containing mouse tumor cells were significantly more sensitive to direct treatment with this drug than were p53-deficient tumor cells. In an attempt to reconcile this apparent discrepancy, we examined the requirement for p53 in the cytotoxic effects of tumor necrosis factor alpha (TNF-alpha), a cytokine released from murine macrophages upon paclitaxel treatment. Conditioned medium from paclitaxel-treated macrophages was capable of inducing p53-independent apoptosis when applied to transformed mouse embryonic fibroblasts and was inhibitable by antibodies against TNF-alpha. Furthermore, in response to direct treatment with TNF-alpha, both wild-type and p53-deficient tumor cells underwent apoptosis to similar extents and with similar kinetics. Our results suggest that the efficacy of paclitaxel in vivo may be due not only to its microtubule-stabilizing activity, but its ability to activate local release of an apoptosis-inducing cytokine.
Insights
Wild-type p53 enhances sensitivity to paclitaxel chemotherapy. However, paclitaxel also triggers tumor necrosis factor-alpha (TNF-alpha), inducing apoptosis independently of p53 status, suggesting a dual mechanism for its efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Tumor cell genotype, specifically p53 gene mutations, influences chemotherapeutic efficacy and resistance.
- Paclitaxel (Taxol) is an antineoplastic agent that stabilizes microtubules and is effective against various human tumor xenografts.
- The role of p53 in mediating cellular responses to paclitaxel and related cytokines requires further investigation.
Purpose of the Study:
- To investigate the role of wild-type p53 in the response of tumor cells to paclitaxel.
- To reconcile the discrepancy between paclitaxel's broad efficacy and the observed p53-dependent sensitivity in vitro.
- To examine the involvement of tumor necrosis factor-alpha (TNF-alpha) in paclitaxel-induced apoptosis.
Main Methods:
- Comparison of paclitaxel sensitivity between p53-containing and p53-deficient mouse tumor cells.
- Assessment of cytotoxic effects of conditioned medium from paclitaxel-treated macrophages.
- Evaluation of apoptosis induction by tumor necrosis factor-alpha (TNF-alpha) in both wild-type and p53-deficient tumor cells.
Main Results:
- p53-containing mouse tumor cells demonstrated significantly higher sensitivity to direct paclitaxel treatment compared to p53-deficient cells.
- Conditioned medium from paclitaxel-treated macrophages induced apoptosis in a p53-independent manner.
- Antibodies against TNF-alpha inhibited the apoptosis-inducing effects of the conditioned medium.
- Both wild-type and p53-deficient tumor cells exhibited similar apoptosis induction and kinetics upon direct TNF-alpha treatment.
Conclusions:
- Paclitaxel's in vivo efficacy may involve both its direct microtubule-stabilizing activity and its capacity to induce local release of apoptosis-inducing cytokines like TNF-alpha.
- The p53 tumor suppressor gene status influences direct sensitivity to paclitaxel but not TNF-alpha-mediated apoptosis.
- These findings highlight a complex interplay between p53, paclitaxel, and cytokine signaling in tumor cell death.