Rb2/p130 and protein phosphatase 2A: key mediators of ovarian carcinoma cell growth suppression by all-trans retinoic acid

Abstract

Despite a number of attempts to improve treatment of ovarian cancer, it remains the most common cause of death from gynecological cancers. Thus, it is very important to identify more effective drugs for treatment and prevention of ovarian cancer. All-trans-retinoic acid (ATRA) has been shown to arrest the growth of ovarian carcinoma cells in G0/G1 and to significantly elevate levels of Rb2/p130 protein, a member of the retinoblastoma family of tumor suppressors. As ATRA treatment leads to a significant increase in the amount of Rb2/p130 protein but not mRNA, the elevated levels of Rb2/p130 protein is likely the result of increased stability. In studies to elucidate the mechanism by which ATRA alters Rb2/ p130 stability in ovarian cancer cells, it was determined that PP2A, a serine/threonine phosphatase, binds and dephosphorylates Rb2/p130. Dephosphorylated Rb2/p130 exhibits decreased ubiquitination and thus is not degraded by the proteasome. The sites at which PP2A catalytic subunit (PP2Ac) interacts with Rb2/p130 have been localized to the NLS in the C-terminus of Rb2/p130. These sites are also involved in the interaction of Rb/p130 with importin b and importin a, members of the nuclear transport machinery. It is known that importin a recognizes a NLS on a target protein and importin b binds the nuclear pore complex. Moreover, it has been shown that the binding of importin a to NLS significantly decreases with phosphorylation of NLS. In ATRA-treated ovarian carcinoma cells, PP2A binds to Rb2/p130 and dephosphorylates the NLS of Rb2/p130 leading to the interaction of importin a with Rb2/p130. Importin b then binds to the importin a-Rb2/p130 complex, leading to the translocation of the Rb2/p130 to the nucleus where it acts to arrest ovarian cancer cells in G1 and suppress proliferation.

Hepatitis B virus X protein overcomes the growth-inhibitory potential of retinoic acid by downregulating retinoic acid receptor- 2 expression via DNA methylation

“…HBx suppresses the anti-growth potential of RA It is widely known that RA inhibits cell growth and induces cell-cycle G 1 arrest (Soprano et al, 2006). In general, RAinduced G 1 arrest is associated with multiple changes in G 1 -checkpoint regulators, i.e.…”

“…In addition, this effect was almost completely abolished by treatment with 5-Aza-29dC. As levels of RAR-a and RAR-c were minimally affected by HBx (data not shown), it is likely that the lower transcriptional activity of RAR in the presence of HBx is primarily due to the downregulation of RAR-b 2 via promoter hypermethylation.HBx suppresses the anti-growth potential of RA It is widely known that RA inhibits cell growth and induces cell-cycle G 1 arrest (Soprano et al, 2006). In general, RAinduced G 1 arrest is associated with multiple changes in G 1 -checkpoint regulators, i.e.…”

Insulin Receptor Substrate-1 Is an Important Mediator of Ovarian Cancer Cell Growth Suppression by All-trans Retinoic Acid

“…Currently, retinoids are used for the treatment of acute promyelocytic leukemia and head and neck cancers (4,5). Reports from several laboratories including ours have shown that retinoids inhibit the growth and cell cycle progression of ovarian carcinoma cell lines (4). Our studies have focused on the effect of all-trans retinoic acid (ATRA) treatment on two ovarian carcinoma cell lines, CA-OV3 and SK-OV3.…”

“…In addition, various retinoids are effective chemotherapeutic and chemopreventive agents for several human cancers. Currently, retinoids are used for the treatment of acute promyelocytic leukemia and head and neck cancers (4,5). Reports from several laboratories including ours have shown that retinoids inhibit the growth and cell cycle progression of ovarian carcinoma cell lines (4).…”

Effects of Retinoic Acid on Proliferation and Differentiation of HepG2 Cells

“…Retinoic acid, a derivative of vitamin A, plays many roles in cell differentiation, proliferation, and apoptosis. Retinoic acid has been shown to cause growth arrest and differentiation in several cancer cell lines [9][10][11][12][13][14]. Retinoic acid has previously been determined to slow HepG2 growth [15,16], and high concentrations (166 μM), induced *Address correspondence to this author at the Department of Biomedical Engineering, 599 Taylor Road, Piscataway, NJ 08854, USA; Tel: 732-445-4500x6205; Fax: 732-445-3753; E-mail: cmroth@rci.rutgers.edu apoptosis [17].…”