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Retinoids and TRAIL: two cooperating actors to fight against cancer
Lucia Altucci1, Hinrich Gronemeyer
1Dipartimento di Patologia Generale Seconda Università degli Studi di Napoli 80138, Napoli, Italy.
Abstract:
Multiple studies performed in in vitro and in vivo settings have confirmed the cancer therapeutic and cancer preventive capacity of retinoids and rexinoids. These compounds mediate their actions through the retinoid and rexinoid receptors, respectively, which exist in multiple isoforms and form a plethora of distinct heterodimers. Despite their apparent anticancer potential, with one exception the molecular basis of this activity has remained largely elusive. The exception concerns acute promyelocytic leukemia (APL), the prototype of retinoic acid-dependent differentiation therapy, for which both the molecular nature of the disease and the mechanism of action of retinoids are well understood. However, retinoids and rexinoids are active beyond the borderlines of the well-defined chromosomal translocation that gives rise to curable APL. In this context, particularly interesting is that retinoic acid induces a member of the tumor necrosis factor family, tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or Apo2L. This ligand is exceptional in that it is capable of inducing apoptosis in cancer cells but not in normal cells. It is possible that this connection to the TRAIL signaling pathway contributes to the anti-tumor activity of retinoids and rexinoids. This review focuses on what is presently known about the regulation of cell life and death by the retinoid/rexinoid and TRAIL signaling pathways.
Insights
Retinoids and rexinoids show anticancer potential by regulating cell death pathways. Their connection to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) may explain their anti-tumor activity.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Retinoids and rexinoids are known for their cancer therapeutic and preventive properties.
- Their mechanisms of action involve retinoid and rexinoid receptors, forming various heterodimers.
- While effective in acute promyelocytic leukemia (APL), their broader anticancer molecular basis is often unclear.
Purpose of the Study:
- To review the regulation of cell life and death by retinoid/rexinoid and TRAIL signaling pathways.
- To explore the potential link between retinoid/rexinoid activity and the TRAIL pathway in cancer therapy.
Main Methods:
- Literature review of in vitro and in vivo studies.
- Analysis of molecular mechanisms underlying retinoid/rexinoid and TRAIL signaling.
- Focus on the induction of TRAIL by retinoic acid.
Main Results:
- Retinoids and rexinoids act via specific receptors and heterodimers.
- Acute promyelocytic leukemia (APL) serves as a model for retinoic acid-dependent differentiation therapy.
- Retinoic acid induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L), which selectively induces apoptosis in cancer cells.
Conclusions:
- The induction of TRAIL by retinoids and rexinoids may contribute to their anti-tumor effects.
- Understanding the interplay between retinoid/rexinoid and TRAIL pathways is crucial for developing novel cancer therapies.
- Further research into these signaling pathways can elucidate broader therapeutic applications beyond APL.
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