Retinoids and TRAIL: two cooperating actors to fight against cancer.
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.
Altucci
Lucia
L
Dipartimento di Patologia Generale Seconda Università degli Studi di Napoli 80138, Napoli, Italy.
Gronemeyer
Hinrich
H
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000473:pathology; D008562:Membrane Glycoproteins / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy / Q000517:prevention & control*; D018168:Receptors, Retinoic Acid / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D047488:Retinoid X Receptors; D012176:Retinoids / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D018808:Transcription Factor AP-1; D014157:Transcription Factors / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D018168:Receptors, Retinoic Acid; D018124:Receptors, Tumor Necrosis Factor; D047488:Retinoid X Receptors; D012176:Retinoids; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha