Carter C A, Pogribny M, Davidson A, Jackson C D, McGarrity L J, Morris S M
Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
Anticancer Res. 1996 Jan-Feb;16(1):17-24.
All-trans retinoic acid is currently used in clinical trials in combination with tamoxifen to treat breast cancer, and 13-cis retinoic acid is used with a-interferon to treat metastatic endometrial cancer. We examined the effects of all-trans retinoic acid and 13-cis RA alone on endometrial adenocarcinoma (RL95-2) cells to investigate the cell biological mechanisms by which retinoic acid may reduce the metastatic phenotype and induce differentiation.
RL95-2 cells were seeded onto 4-chamber plastic slides and treated with 13-cis retinoic acid or all-trans retinoic at 0.5 microM, 1 microM and 5 microM doses for 90 minutes at 37 degrees C and stained for F-actin.
Untreated RL95-2 cells exhibited staining of disrupted aggregates of F-actin only near the cell periphery. Cells treated with the three doses of 13-cis retinoic acid exhibited a dramatic reorganization of F-actin throughout the cells. When cells were treated with 0.5 microM all-trans retinoic acid, actin filaments reorganized. Cells treated with 1 microM all-trans retinoic acid and 5 microM all-trans retinoic acid displayed increased organization of F-actin and cell size increased. The percentage of S-phase cells increased at the high doses of retinoic acid treatment. This effect was apparently transient, since retinoic acid did not significantly affect cell growth.
An organized cytoskeleton and an increase in cell size are associated with differentiation. We suggest that retinoic acid exerts its effects on these transformed cells by reorganizing actin filaments, and inducing differentiation, thus inducing a more stationary phenotype.
全反式维甲酸目前正与他莫昔芬联合用于乳腺癌的临床试验，而13-顺式维甲酸则与α-干扰素联合用于治疗转移性子宫内膜癌。我们研究了全反式维甲酸和13-顺式维甲酸单独对子宫内膜腺癌（RL95-2）细胞的影响，以探讨维甲酸可能降低转移表型并诱导分化的细胞生物学机制。
将RL95-2细胞接种到4孔塑料载玻片上，分别用0.5微摩尔/升、1微摩尔/升和5微摩尔/升剂量的13-顺式维甲酸或全反式维甲酸在37℃处理90分钟，然后进行F-肌动蛋白染色。
未处理的RL95-2细胞仅在细胞周边附近显示出F-肌动蛋白聚集物的破坏染色。用三种剂量的13-顺式维甲酸处理的细胞在整个细胞中表现出F-肌动蛋白的显著重组。当细胞用0.5微摩尔/升全反式维甲酸处理时，肌动蛋白丝发生重组。用1微摩尔/升和5微摩尔/升全反式维甲酸处理的细胞显示F-肌动蛋白的组织性增加，细胞大小增大。高剂量维甲酸处理时S期细胞百分比增加。这种作用显然是短暂的，因为维甲酸对细胞生长没有显著影响。
有组织的细胞骨架和细胞大小增加与分化相关。我们认为维甲酸通过重组肌动蛋白丝并诱导分化，从而对这些转化细胞发挥作用，进而诱导出更稳定的表型。
