Role of Mitochondria and Caspases in Vitamin D-mediated Apoptosis of MCF-7 Breast Cancer Cells

Narvaez, Carmen J.; Welsh, JoEllen

doi:10.1074/jbc.m006876200

Cited by 165 publications

(102 citation statements)

References 33 publications

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“…In addition, although we have shown in this report that VD3 compounds induced caspase activation and PARP cleavage (Figure 4c), it has been reported that apoptosis induced by VD3 compounds could also be involved in caspase-independent pathway (Mathiasen et al, 1999;Narvaez and Welsh, 2001). Consistent with these reports, it has been shown that apoptotic cell death triggered by downregulation of survivin could also be involved in both caspase-dependent and caspase-independent pathways (Shankar et al, 2001;Li, 2003;Liu et al, 2004).…”

Section: Discussionsupporting

confidence: 75%

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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Section: Discussionsupporting

confidence: 75%

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 calbindin-D 28k in some models has been shown to confer protection against apoptosis by directly inhibiting caspases, such a mode of action is, however, unlikely in our model system because the death is independent of known caspases (4,16,17,52). Furthermore, MCF-7 cells expressing calbindin-D 28k were as sensitive as the control cells to death receptor-induced caspase-dependent apoptosis.…”

Section: Discussionmentioning

confidence: 81%

Calcium and Calpain as Key Mediators of Apoptosis-like Death Induced by Vitamin D Compounds in Breast Cancer Cells

Mathiasen¹,

Сергеев²,

Bastholm³

et al. 2002

Journal of Biological Chemistry

194

167

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Very little is known about the signaling pathways mediating vitamin D-induced cell death. A single family of proteases, the caspases, has until recently been considered the pivotal executioner of all programmed cell death (8). Therefore it is interesting to note that breast cancer cells treated with vitamin D compounds die in the complete absence of effector caspase activation (4). Despite the lack of the caspase activation, dying cells present several characteristics of apoptosis, i.e. rounding, shrinkage, and detachment of cells as well as DNA strand breaks and DNA fragmentation (4, 9, 10). Furthermore, antiapoptotic proteins Bcl-2 and Bcl-X L can rescue breast cancer cells from death induced by the active form of vitamin D or its analogs (4). This apoptosis-like death program appears also independent of cysteine cathepsins and p53 tumor suppressor protein (4, 11). Instead, the elevation in the intracellular free calcium ([Ca 2ϩ ] i ) brought about by vitamin D compounds correlates with the induction of apoptosis in breast cancer cells (9,12,13).Data from studies employing various pharmaceutical modulators of calcium homeostasis have suggested that the elevation in [Ca 2ϩ ] i is a sufficient signal to induce apoptosis in several model systems, even though it may also have the opposite effect in other systems (14). Further supporting the idea that the elevation in [Ca 2ϩ ] i may mediate apoptosis, studies based on modulated expression of calcium-binding proteins, calbindin-D 28k or glucose-regulated proteins GRP78 and GRP94, have shown that Ca 2ϩ buffering can confer protection against various apoptotic stimuli (15-19). The calcium-dependent neutral cysteine proteases, calpains, are frequently activated in apoptosis models involving elevated [Ca 2ϩ ] i (20 -22). Two forms of calpains, -calpain and m-calpain or type I and type II calpain, respectively, are ubiquitously expressed in human cells (23)(24)(25). The active forms of the enzymes consist of a variable large subunit (80 kDa) and a common small subunit (30 kDa). To become active, calpains require an elevation in [Ca 2ϩ ] i , and the autoproteolytic cleavage of the enzymes further enhances their activity. Whereas m-calpain requires Ca 2ϩ at a millimolar range, micromolar concentrations are enough for the activation of -calpain (in vitro; lower in cells). So far no difference in the substrate specificity of the two isozymes has been found. Growing evidence suggests that calpains may play a central role in the execution of apoptosis either upstream or * This work was supported by the Danish Medical Research Council, the Danish Cancer Society (to I. S. M. and M. J.), and by Grant CA67317 from the NCI, National Institutes of Health (to I. N. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. § Present address: Molecular Biology, Novo Nordisk A/S, Bagsvaerd DK 2880, Denmar...

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“…Similarly some studies have shown that vitamin D3 had a modulatory effects (upregulation of proapoptotic genes or down-regulation of proantiptotic genes) on apoptosis related genes (Narvaez et al, 2001;Pirianov et al, 2001;Kizildağ et al, 2010). In a study, it was mentioned close cooperation between VDR action and p53 tumor suppressor pathway (Patel et al, 2012).…”

Section: Discussionmentioning

confidence: 86%

Is Season a Prognostic Factor in Breast Cancer?

Mutlu¹,

Akca²,

Cihan³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Some studies have indicated an inverse relationship between cancer risk and sunlight exposure. Others have reported that the prognosis of some cancers such as prostate, colon, ovarian and non melanoma skin cancer, were affected by the season in which the cancer was diagnosed. In our study, we evaluated whether season is prognostic in Turkish patients with breast cancer. Materials and Methods: A total of 517 patients from Kayseri Training and Research Hospital were analysed retrospectively. Patients were divided into 4 groups according to season of cancer diagnosis: winter, spring, summer and autumn. The prognostic factors for disease free survival and overall survival were investigated. Results: No significant differences were found among groups regarding prognostic factors overall. Only estrogen receptor status and lymphovascular invasion were independent prognostic factors (p=0.001 and p=0.001 respectively). We found significantly differences for mean disease free survival among groups (p=0.019). Winter group had better mean DFS while summer group had worse DFS. Mean overall survival was similar in the four groups (p=0.637). Conclusions: The season is not an independent predictive factor. However, due to interaction with other factors, we think that the season of cancer diagnosis is important for cancer prognosis.

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Role of Mitochondria and Caspases in Vitamin D-mediated Apoptosis of MCF-7 Breast Cancer Cells

Cited by 165 publications

References 33 publications

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

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

Calcium and Calpain as Key Mediators of Apoptosis-like Death Induced by Vitamin D Compounds in Breast Cancer Cells

Is Season a Prognostic Factor in Breast Cancer?

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