前列腺癌(PC)组织含有全反式维甲酸(ATRA)在非常低的水平(10-9M),至少比相邻的正常健康前列腺细胞或良性前列腺增生低一个数量级。当这与经常在PC中发现的细胞内脂质结合蛋白FABP5和CRABP2的表达失调相关时,这可能导致ATRA优先递送至致癌PPARβ/δ,而不是视黄酸受体(RAR).有三种同种型的RAR(RARα,RARβ,和RARγ)和最近的研究揭示了离散的生理作用。例如,RARα和RARγ促进分化和自我更新,分别,这对正常的造血至关重要。
我们之前已经表明,ATRA在亚纳摩尔浓度(EC500.24nM)下刺激RARγ的反式激活,而RARα介导的反式激活需要80倍以上的浓度(EC5019.3nM)。此外,我们已经证明RAR泛拮抗剂抑制PC细胞的生长(在16-34nM)。这些发现,加上PC中ATRA的低水平,导致我们假设RARγ在PC发病机制中起作用,并且RARγ选择性拮抗可能是一种有效的治疗方法。
我们发现10-9μM及以下浓度的ATRA通过涉及RARγ的机制促进人PC细胞系的存活/增殖和相反的成脂分化。我们还发现,RARγ选择性拮抗剂(AGN205728)有效诱导线粒体依赖性,但是caspase是独立的,PC细胞系中的细胞死亡。此外,AGN205728与细胞毒性化疗剂组合在杀死PC细胞中表现出协同作用。
我们建议使用RARγ选择性拮抗剂可能对PC(以及潜在的其他癌症)有效。作为单一药物或与细胞毒性化疗联合使用。
Prostate cancer (PC) tissue contains all-trans retinoic acid (ATRA) at a very low level (10-9 M), at least an order of magnitude lower than in adjacent normal healthy prostate cells or benign prostate hyperplasia. When this is coupled with deregulated expression of the intracellular lipid-binding proteins FABP5 and CRABP2 that is frequently found in PC, this is likely to result in the preferential delivery of ATRA to oncogenic PPARβ/δ rather than retinoic acid receptors (RARs). There are three isotypes of RARs (RARα, RARβ, and RARγ) and recent studies have revealed discrete physiological roles. For example, RARα and RARγ promote differentiation and self-renewal, respectively, which are critical for proper hematopoiesis.
We have previously shown that ATRA stimulates transactivation of RARγ at sub-nanomolar concentrations (EC50 0.24 nM), whereas an 80-fold higher concentration was required for RARα-mediated transactivation (EC50 19.3 nM). Additionally, we have shown that RAR pan-antagonists inhibit the growth of PC cells (at 16-34 nM). These findings, together with the low level of ATRA in PC, led us to hypothesize that RARγ plays a role in PC pathogenesis and that RARγ-selective antagonism may be an effective treatment.
We found that concentrations of 10-9 M and below of ATRA promoted survival/proliferation and opposed adipogenic differentiation of human PC cell lines by a mechanism that involves RARγ. We also found that a RARγ-selective antagonist (AGN205728) potently induced mitochondria-dependent, but caspase-independent, cell death in PC cell lines. Furthermore, AGN205728 demonstrated synergism in killing PC cells in combination with cytotoxic chemotherapeutic agents.
We suggest that the use of RARγ-selective antagonists may be effective in PC (and potentially other cancers), either as a single agent or in combination with cytotoxic chemotherapy.