Activation of the human FP prostanoid receptor disrupts mitosis progression and generates aneuploidy and polyploidy.
Studies have shown prostaglandin F(2alpha) (PGF(2alpha)) to be an endogenous tumor promoter in mouse models of skin carcinogenesis; however, the mechanisms by which PGF(2alpha) affects cell cycle events remain unknown. Here we performed cell cycle analyses on HEK cells stably expressing the human FP receptor and found that treatment with PGF(2alpha) delays mitosis and is associated with an increased expression of cyclin B1 and Cdc2 kinase activity. In addition, multipolar spindles and misaligned chromosomes were observed in a significant proportion of cells treated with PGF(2alpha). Defective cytokinesis was also observed which resulted in gross aneuploidy and polyploidy. Expression of dominant negative Rho attenuated the cell cycle delay and prevented the generation of micronuclei following treatment with PGF(2alpha). This suggests that FP receptor activation of Rho signaling by PGF(2alpha) can interfere with nuclear division. Aneuploidy is associated with genomic instability and may underlie the tumor-promoting properties of PGF(2alpha).
Chen
X-B
XB
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721-0207, USA.
Regan
J W
JW
D000782:Aneuploidy; D002460:Cell Line; D016764:Cell Polarity / Q000187:drug effects; D002877:Chromosomes, Human / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D015237:Dinoprost / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D011123:Polyploidy; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; D015237:Dinoprost; D020741:rho GTP-Binding Proteins