Retinoic acid-mediated growth arrest of EBV-immortalized B lymphocytes is associated with multiple changes in G1 regulatory proteins: p27Kip1 up-regulation is a relevant early event

Zancai, Paola; Cariati, Roberta; Rizzo, Silvana; Boiocchi, Mauro; Dolcetti, Riccardo

doi:10.1038/sj.onc.1202089

Cited by 31 publications

(32 citation statements)

References 25 publications

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“…This pattern became apparent by day 3, which corresponded to the start of growth inhibition. These results are consistent with other reports which show that RA causes hypophosphorylation of RB in various cell lines (Matsuo and Thiele, 1998;Naderi and Blomho , 1999;Seewaldt et al, 1999;Spinella et al, 1999;Sueoka et al, 1999;Teixeira and Pratt, 1997;Watanabe et al, 1999;Wilcken et al, 1996;Zancai et al, 1998). For example, Wilcken et al (1996) reported hypophosphorylation of RB in T-47D breast cancer cells upon RA treatment.…”

Section: Discussionsupporting

confidence: 83%

“…Since cdk 2 is the partner for cyclin E, it is likely that the RA-dependent increase in p27 results in increased binding of the cyclin E/cdk 2 complex by p27, leading to decreased cyclin E/cdk 2 kinase activity and, as a consequence, hypophosphorylation of RB in mid to late G-1. This idea is supported by studies which suggest that p27 up-regulation could be a primary response in RA treated cells (Borriello et al, 2000;Matsuo and Thiele, 1998;Weber et al, 1999;Zancai et al, 1998;Zhu et al, 1997). Interestingly this upregulation is at the protein level but not at the mRNA level (Borriello et al, 2000;Matsuo and Thiele, 1998;Zancai et al, 1998).…”

Section: Discussionsupporting

confidence: 65%

“…This idea is supported by studies which suggest that p27 up-regulation could be a primary response in RA treated cells (Borriello et al, 2000;Matsuo and Thiele, 1998;Weber et al, 1999;Zancai et al, 1998;Zhu et al, 1997). Interestingly this upregulation is at the protein level but not at the mRNA level (Borriello et al, 2000;Matsuo and Thiele, 1998;Zancai et al, 1998). Borriello et al (2000) showed that the accumulation of p27 is due to increased proteasome-dependent degradation.…”

Section: Discussionsupporting

confidence: 63%

“…Fifty micrograms of protein samples, prepared as described in Materials and methods, were loaded on 15% SDS ± PAGE gels and assayed by Western blotting using antibodies to p27 and p16. Zancai et al, 1998). However, neither study determined the phosphorylation status of the RB-2/ p130.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, there is very limited knowledge about the e ect of RA on RB-2/p130 expression and phosphorylation. Within the past few years, there are only a few reports which describe changes of RB-2/p130 protein level after RA treatment (Hsu et al, 1997;Li et al, 1998;Zancai et al, 1998;Baldassarre et al, 2000). Two studies described an increase in RB-2/p130 in NT2/D1 embryonal carcinoma cells and B-lymphoblastoid cell lines respectively after RA treatment (Baldassarre et Figure 5 Kinase assays to determine Cdk 2, Cdk 4 and Cdk 6 kinase activity after RA treatment of CA-OV3 cells.…”

Section: Discussionmentioning

confidence: 99%

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Cell cycle genes as targets of retinoid induced ovarian tumor cell growth suppression

et al. 2001

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 65%

Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cell cycle genes as targets of retinoid induced ovarian tumor cell growth suppression

et al. 2001

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Retinoic acid induces persistent, RAR?-mediated anti-proliferative responses in Epstein-Barr virus-immortalized b lymphoblasts carrying an activated c-myc oncogene but not in Burkitt's lymphoma cell lines

et al. 2000

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We have previously demonstrated that 13‐cis‐retinoic acid (RA), 9‐cis‐RA and all‐trans‐RA (ATRA) powerfully inhibit the proliferation of Epstein‐Barr virus–immortalized B‐lymphoblastoid cell lines (LCLs). The aim of the present study was to assess whether these compounds are effective at inhibiting the growth of B cells at more advanced stages of lymphomagenesis, including fully transformed B lymphocytes. To this end, c‐myc–transfected LCLs (myc‐LCLs) and Burkitt's lymphoma (BL) cell lines were used. We report that 13‐cis‐RA, 9‐cis‐RA and ATRA also markedly inhibit the proliferation of myc‐LCLs by inducing G0/G1 growth arrest as well as enhancing rates of apoptosis. Conversely, all but 1 (DG75) of the 8 BL cell lines investigated were poorly RA‐responsive. Moreover, unlike LCLs and myc‐LCLs, RA‐treated DG75 cells rapidly resumed proliferation upon drug removal. Analysis of cell cycle–regulatory proteins showed that, as in LCLs, strong up‐regulation of p27Kip−1 and increased levels of under‐phosphorylated pRb and p130 were detected in RA‐treated DG75 cells. While the catalytic activity of all 3 G1‐associated CDKs (CDK2, CDK4 and CDK6) was strongly inhibited in RA‐treated LCLs, only CDK2‐associated kinase activity was reduced in DG75 cells arrested in G0/G1 by RA. Moreover, RA‐treated DG75 cells failed to show the down‐regulation of cyclin D3 observed in LCLs. Use of receptor‐selective agonists and antagonists showed that in LCLs and RA‐responsive BL cells, RA‐induced growth arrest is mainly mediated by RARα. The RARα‐selective agonist Ro 40‐6055 was also effective at very low concentrations (10–10 M). Nevertheless, comparable levels of RARα mRNA were found in RA‐responsive and ‐resistant BL cell lines, indicating that mechanisms different from transcriptional deregulation of RARα probably underlie the differential responsiveness of BL cells. Int. J. Cancer 86:375–384, 2000. © 2000 Wiley‐Liss, Inc.

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Retinoids and ovarian cancer

Zhang

Holmes

et al. 2000

J. Cell. Physiol.

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Each year, an estimated 26,000 women in the United States are diagnosed with ovarian cancer. During any given year, approximately 14,500 women die from this disease. Ovarian cancer is the seventh most common cancer in women worldwide, after breast, cervix, colon/rectum, stomach, corpus uteri, and lung cancers. In the U.S., ovarian cancer is the second most common gynecologic cancer, and is the fourth leading cause of solid tumor cancer deaths among women. Currently, postoperative chemotherapy of ovarian cancer is still suboptimal. Drug resistance is a common problem resulting in only 20 approximately 30% overall 5-year survival rates. Clearly, continued development of alternative therapeutic strategies is essential for the management of this fatal disease. A number of recent studies have suggested that retinoids may play a potential role as an ovarian cancer chemotherapeutic agent. Retinoids, the natural and synthetic derivatives of vitamin A, have been shown to inhibit the growth of human ovarian cancer cells both in vivo and in culture. This review will initially summarize what is known about the pathological and molecular characteristics of ovarian carcinoma. It will then describe retinoid metabolism and the role of the cellular and nuclear retinoid binding proteins in mediating retinoid action. Following this general review of retinoids and their function, data supporting the role of retinoic acid as a suppresser of ovarian carcinoma cell growth will be presented. Particular attention will be paid to studies suggesting that members of the RB family of proteins and RB2/p130, in particular, are the molecular targets responsible for retinoid mediated inhibition of ovarian carcinoma cell growth. This review will then conclude with a brief discussion of two synthetic retinoids, 4 HPR R(fenretinide) and AHPN/CD437, which have been shown to induce apoptosis in ovarian tumor cells. It will be clear from the studies summarized in this review that retinoids represent a potentially powerful alternative to present chemotherapeutic approaches to the treatment of late stage ovarian cancer.

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Retinoic acid-mediated growth arrest of EBV-immortalized B lymphocytes is associated with multiple changes in G1 regulatory proteins: p27Kip1 up-regulation is a relevant early event

Cited by 31 publications

References 25 publications

Cell cycle genes as targets of retinoid induced ovarian tumor cell growth suppression

Cell cycle genes as targets of retinoid induced ovarian tumor cell growth suppression

Retinoic acid induces persistent, RAR?-mediated anti-proliferative responses in Epstein-Barr virus-immortalized b lymphoblasts carrying an activated c-myc oncogene but not in Burkitt's lymphoma cell lines

Retinoids and ovarian cancer

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