Vitamin D analogues up-regulate p21 and p27 during growth inhibition of pancreatic cancer cell lines

Kawa, Shigeyuki; Nikaido, Toshio; Aoki, Yuji; Zhai, Yali; Kumagai, Toshiko; Furihata, Kenichi; Fujii, Shingo; Kiyosawa, Kendo

doi:10.1038/bjc.1997.479

Cited by 111 publications

(86 citation statements)

References 22 publications

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“…A number of genes are regulated by 1,25D 3 and its analogues, including the cyclin-dependent kinase inhibitors (CDKI) p21 WAF-1 and p27 Kip1 (Liu et al, 1996;Wang et al, 1996;Matsumoto et al, 1998). Both these proteins have been shown to be up-regulated in the pancreatic cancer cell line BxPc-3 after treatment with 1,25D 3 as well as the synthetic analogue 22-oxa-1,25-dihydroxyvitamin D 3 (OCT) (Kawa et al, 1997), implying that this is the mechanism whereby G0/G1 arrest is achieved. p21 WAF-1 can also protect cells from apoptosis in some systems (Gartel and Tyner, 1999).…”

Section: Discussionmentioning

confidence: 99%

Differential and antagonistic effects of 9-cis-retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro

2000

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Retinoids and vitamin D are known to exert important anti-tumour effects in a variety of cell types. In this study the effects of 9- cis -retinoic acid (9cRA) the vitamin D analogues EB1089 and CB1093 on three pancreatic adenocarcinoma cell lines were investigated. All compounds caused inhibition of in vitro growth but the vitamin D analogues were generally the more potent growth inhibitors. They were also more effective on their own than in combination with 9cRA. Growth arrest correlated with an increased proportion of cells in the G0/G1 phase. Apoptosis was induced in the three cell lines by 9cRA, whereas neither EB1089 nor CB1093 had this effect. Furthermore, addition of EB1089 or CB1093 together with 9cRA resulted in significantly reduced apoptosis. Our results show that retinoic acids as well as vitamin D analogues have inhibitory effects on pancreatic tumour cells but different and antagonistic mechanisms seem to be employed. © 2000 Cancer Research Campaign

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Section: Discussionmentioning

confidence: 99%

Differential and antagonistic effects of 9-cis-retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro

2000

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“…However, the mechanisms by which these compounds generate inhibition of proliferation and induction of apoptosis in tumor cells are not fully understood. The inhibition of cell proliferation mediated by VD3 compounds has been reported to be due to modulation of cell cycle regulators and a G1 phase arrest through induction of p21 and p27 in pancreatic and breast cancer cells (Kawa et al, 1997;Wu et al, 1997;Verlinden et al, 1998). However, another report showed that VD3-induced G1 arrest is associated with a significant decrease of p21 and increase of p27 in squamous cell carcinoma cells (Hershberger et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines

Ling

Huang

et al. 2004

Oncogene

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Although both the antiapoptotic function of survivin and vitamin D 3 (VD3)-mediated cell growth inhibition and apoptosis have been extensively studied, it is not known whether survivin plays a role in VD3 compound-mediated cell growth inhibition and apoptosis induction. Using an isogenic model of MCF-7 breast adenocarcinoma cells (MCF-7E and MCF-7L sublines that are sensitive and resistant to VD3 compounds), we found that VD3 compounds effectively downregulated survivin in VD3-sensitive MCF-7E cells, which was associated with VD3-induced apoptosis. In contrast, VD3 compounds failed to downregulate survivin in VD3-resistant MCF-7L cells, which showed resistant to VD3-induced apoptosis. However, inhibition of survivin expression by small interfering RNA (siRNA) induced cell death per se and further sensitized VD3-induced apoptosis in MCF-7L cells, indicating that the inability of these cells to respond to VD3 is due to the failure to downregulate survivin. Forced expression of survivin not only blocked VD3-mediated G1 cell accumulation but also increased S and G2/M cell populations. VD3 treatment rapidly triggered the activation of p38 MAPK signaling in MCF-7E cells but not in MCF-7L cells. Moreover, inhibition of p38 activation diminished VD3-mediated survivin inhibition and partially rescued VD3-induced cell death. We further showed that VD3 increased the expression of TGFb1 and TGFb receptor 2, and that blocking the function of TGFb receptor 2 diminished VD3 compound-mediated survivin downregulation. Thus, we propose that the VD3 compound-induced growth inhibition and apoptosis induction are at least partially dependent on survivin downregulation via VD3-induced TGFb signaling and the activation of p38 MAPK pathway. Targeting survivin through these pathways may lead to novel applications for cancer therapeutics.

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“…For example, increased expression of both p21Waf1 and p27Kip1 protein has been observed upon di erentiation of myeloid cells, prostate cells, glioma, oligodendrocytes and erythroid progenitors (Chen et al, 1999;Ghiani et al, 1999;Harvat et al, 1998;Muto et al, 1999;Panzenbock et al, 1998;Zi and Agarwal, 1999) and in vitamin D-induced arrest of tumor cells (Kawa et al, 1997). In normal keratinocyte (Harvat et al, 1998) and megakaryocyte (Taniguchi et al, 1999;Urashima et al, 1997) di erentiation, p21Waf1 upregulation immediately precedes increased levels of p27Kip1 protein.…”

Section: Introductionmentioning

confidence: 99%

Cell cycle-independent upregulation of p27Kip1 by p21Waf1 in K562 cells

Steinman

Yaroslavskiy

et al. 2001

Oncogene

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Cellular di erentiation frequently involves sequential peaks in the expression of cyclin-dependent kinase inhibitors (cdki's). For example, an increase in levels of the cdki p27Kip1 follows upregulation of p21Waf1 in several cell types induced to di erentiate by diverse stimuli. In this study, we have investigated whether p21Waf1 expression itself, rather than the di erentiating agent, could be increasing p27Kip1 protein levels. We used an inducible p21Waf1 expression vector in a K562 leukemic cell model which we had previously shown to initiate di erentiation following p21Waf1 upregulation. The current study reports that p21Waf1 upregulated p27Kip1 protein without altering p27Kip1 mRNA levels. This e ect did not depend on G1-phase arrest ± the increase in p27Kip1 occurred at all phases of the cell cycle. p21Waf1-expressing extracts inhibited phosphorylation of p27Kip1 on threonine-187, leading to decreased ubiquitination and decreased proteasomal destruction of p27Kip1. In K562 cells, upregulation of p27Kip1 by p21Waf1 during di erentiation facilitated an ordered transition between these two cdki's, each of which may distinctly in¯uence the di erentiation process. Oncogene (2001) 20, 6524 ± 6530.

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Vitamin D analogues up-regulate p21 and p27 during growth inhibition of pancreatic cancer cell lines

Cited by 111 publications

References 22 publications

Differential and antagonistic effects of 9-cis-retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro

Differential and antagonistic effects of 9-cis-retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro

Differential regulation of survivin expression and apoptosis by vitamin D3 compounds in two isogenic MCF-7 breast cancer cell sublines

Cell cycle-independent upregulation of p27Kip1 by p21Waf1 in K562 cells

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