Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
PPAR Res. 2008;2008:181047. doi: 10.1155/2008/181047.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily. The activation of PPARs by their specific ligands is regarded as one of the promising strategies to inhibit cancer cell growth. However, recent clinical trials targeting several common cancers showed no beneficial effect when PPAR ligands are used as a monotherapy. Retinoid X receptors (RXRs), which play a critical role in normal cell proliferation as a master regulator for nuclear receptors, preferentially form heterodimers with PPARs. A malfunction of RXRalpha due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of certain types of human malignancies. The activation of PPARgamma/RXR heterodimer by their respective ligands synergistically inhibits cell growth, while inducing apoptosis in human colon cancer cells when the phosphorylation of RXRalpha was inhibited. We herein review the synergistic antitumor effects produced by the combination of the PPAR, especially PPARgamma, ligands plus other agents, especially retinoids, in a variety of human cancers. We also focus on the phosphorylation of RXRalpha because the inhibition of RXRalpha phosphorylation and the restoration of its physiological function may activate PPAR/RXR heterodimer and, therefore, be a potentially effective and critical strategy for the inhibition of cancer cell growth.
过氧化物酶体增殖物激活受体 (PPARs) 是核受体超家族的成员。其特定配体激活 PPARs 被认为是抑制癌细胞生长的有前途的策略之一。然而，最近针对几种常见癌症的临床试验表明，当 PPAR 配体作为单一疗法使用时，并没有有益的效果。视黄酸受体 (RXRs) 作为核受体的主调控因子，在正常细胞增殖中发挥着关键作用，优先与 PPAR 形成异二聚体。由于 Ras/MAPK 信号通路的磷酸化，RXRalpha 的功能失常与某些类型的人类恶性肿瘤的发展有关。其各自配体激活的 PPARgamma/RXR 异二聚体协同抑制细胞生长，而当 RXRalpha 的磷酸化被抑制时，诱导人结肠癌细胞凋亡。我们在此综述了 PPAR，特别是 PPARgamma 配体与其他药物（特别是类视黄醇）联合使用在各种人类癌症中产生的协同抗肿瘤作用。我们还重点关注 RXRalpha 的磷酸化，因为抑制 RXRalpha 的磷酸化和恢复其生理功能可能会激活 PPAR/RXR 异二聚体，因此可能是抑制癌细胞生长的一种潜在有效和关键策略。
