Rottlerin inhibits the nuclear factor κB/Cyclin-D1 cascade in MCF-7 breast cancer cells

Torricelli, Claudia; Fortino, Vittoria; Capurro, E.; Valacchi, Giuseppe; Pacini, A.; Muscettola, Michela; Souček, Karel; Maioli, Emanuela

doi:10.1016/j.lfs.2007.12.020

Cited by 41 publications

(52 citation statements)

References 22 publications

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“…This nuclear export decreases the BRCA1-dependent expression of p21. Furthermore, CaMKII stimulates cyclin D1 expression in breast cancer cells via nuclear factor kappaB [46]. Conversely, over-expression of the endogeneous CaMKII inhibitory proteins hCaMKIINalpha and -beta in human colon adenocarcinoma [47] and ovarian cancer cells [48], respectively, stabilizes p27 or up-regulates p21 and downregulates cyclin A, cyclin D1, cyclin E, and Cdk2.…”

Section: Discussionmentioning

confidence: 99%

Non-Selective Cation Channel-Mediated Ca2+-Entry and Activation of Ca2+/Calmodulin-Dependent Kinase II Contribute to G2/M Cell Cycle Arrest and Survival of Irradiated Leukemia Cells

Heise

Palme

Misovic

et al. 2010

Cell Physiol Biochem

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Genotoxic stress induces cell cycle arrest and DNA repair which may enable tumor cells to survive radiation therapy. Here, we defined the role of Ca²⁺ signaling in the cell cycle control and survival of chronic myeloid leukemia (CML) cells subjected to ionizing radiation (IR). To this end, K562 erythroid leukemia cells were irradiated (0-10 Gy). Tumor survival was analyzed by clonogenic survival assay and cell cycle progression via flow cytometry. Plasma membrane cation conductance was assessed by patch-clamp whole-cell recording and the cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) was measured by fura-2 Ca²⁺ imaging. Nuclear activity of Ca²⁺/calmodulin-dependent kinase II (CaMKII) was defined by Western blotting. In addition, the effect of IR (5 Gy) on the cation conductance of primary CML cells was determined. The results indicated that IR (10 Gy) induced a G₂/M cell cycle arrest of K562 cells within 24 h post-irradiation (p.i.) and decreased the clonogenic survival to 0.5 % of that of the control cells. In K562 cells, G₂/M cell cycle arrest was preceded by activation of TRPV5/6-like nonselective cation channels in the plasma membrane 1-5 h p.i., resulting in an elevated Ca²⁺ entry as evident from fura-2 Ca²⁺ imaging. Similarly, IR stimulated a Ca²⁺-permeable nonselective cation conductance in primary CML cells within 2-4 h p.i.. Ca²⁺ entry, into K562 cells was paralleled by an IR-induced activation of nuclear CaMKII. The IR-stimulated accumulation in G₂ phase was delayed upon buffering [Ca²⁺]_i with the Ca²⁺ chelator BAPTA-AM or inhibiting CaMKII with KN93 (1 nM). In addition, KN93 decreased the clonogenic survival of irradiated cells but not of control cells. In conclusion, the data suggest that IR-stimulated cation channel activation, Ca²⁺ entry and CaMKII activity participate in control of cell cycle progression and survival of irradiated CML cells.

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Section: Discussionmentioning

confidence: 99%

Non-Selective Cation Channel-Mediated Ca2+-Entry and Activation of Ca2+/Calmodulin-Dependent Kinase II Contribute to G2/M Cell Cycle Arrest and Survival of Irradiated Leukemia Cells

Heise

Palme

Misovic

et al. 2010

Cell Physiol Biochem

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“…Similarly, rottlerin sensitized glioma cells to TRAIL-mediated apoptosis via down-regulation of Cdc2 (cell cycle division 2) and subsequent suppression of XIAP (X-chromosome-linked IAP) and survivin [14]. Rottlerin inhibited the NF-κB and cyclin D1 in MCF-7 breast cancer cells, leading to cell proliferation inhibition [15]. Controversially, one study showed that rottlerin enhanced oncoprotein COX-2 (cyclooxygenase-2) expression via sustained p38 MAPK (mitogen-activated protein kinase) activation in breast cancer cells [16], suggesting that further investigation is required to determine the function of rottlerin in tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Rottlerin exerts its anti-tumor activity through inhibition of Skp2 in breast cancer cells

Yin

Hou

et al. 2016

Oncotarget

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Studies have investigated the tumor suppressive role of rottlerin in carcinogenesis. However, the molecular mechanisms of rottlerin-induced anti-tumor activity are largely unclear. Skp2 (S-phase kinase associated protein 2) has been validated to play an oncogenic role in a variety of human malignancies. Therefore, inactivation of Skp2 could be helpful for the treatment of human cancers. In the current study, we explore whether rottlerin could inhibit Skp2 expression, leading to inhibition of cell growth, migration and invasion in breast cancer cells. We found that rottlerin treatment inhibited cell growth, induced apoptosis and cell cycle arrest. We also revealed that rottlerin suppressed cell migration and invasion in breast cancer cells. Mechanically, we observed that rottlerin significantly down-regulated the expression of Skp2 in breast cancer cells. Importantly, overexpression of Skp2 abrogated rottlerin-mediated tumor suppressive activity, whereas down-regulation of Skp2 enhanced rottlerin-triggered anti-tumor function. Strikingly, we identified that rottlerin exhibited its anti-tumor potential partly through inactivation of Skp2 in breast cancer. Our findings indicate that rottlerin could be a potential safe agent for the treatment of breast cancer.

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“…Similarly, rottlerin induced apoptosis through upregulation of DR5 (death receptor 5) via PKCδ-independent pathway in human malignant tumor cells [14]. Mechanistically, rottlerin was reported to inhibit the NF-κB (nuclear factor kappa B)/cyclin D1 cascade in breast cancer cells [15]. Moreover, Ohno et al found that rottlerin stimulates apoptosis in pancreatic cancer cells through disrupting the interactions between prosurvival Bcl-2 proteins and proapoptotic BH3-only proteins [16].…”

Section: Introductionmentioning

confidence: 99%

Rottlerin inhibits cell growth and invasion via down-regulation of Cdc20 in glioma cells

et al. 2016

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Rottlerin, isolated from a medicinal plant Mallotus phillippinensis, has been demonstrated to inhibit cellular growth and induce cytoxicity in glioblastoma cell lines through inhibition of calmodulin-dependent protein kinase III. Emerging evidence suggests that rottlerin exerts its antitumor activity as a protein kinase C inhibitor. Although further studies revealed that rottlerin regulated multiple signaling pathways to suppress tumor cell growth, the exact molecular insight on rottlerin-mediated tumor inhibition is not fully elucidated. In the current study, we determine the function of rottlerin on glioma cell growth, apoptosis, cell cycle, migration and invasion. We found that rottlerin inhibited cell growth, migration, invasion, but induced apoptosis and cell cycle arrest. Mechanistically, the expression of Cdc20 oncoprotein was measured by the RT-PCR and Western blot analysis in glioma cells treated with rottlerin. We observed that rottlerin significantly inhibited the expression of Cdc20 in glioma cells, implying that Cdc20 could be a novel target of rottlerin. In line with this, over-expression of Cdc20 decreased rottlerin-induced cell growth inhibition and apoptosis, whereas down-regulation of Cdc20 by its shRNA promotes rottlerin-induced anti-tumor activity. Our findings indicted that rottlerin could exert its tumor suppressive function by inhibiting Cdc20 pathway which is constitutively active in glioma cells. Therefore, down-regulation of Cdc20 by rottlerin could be a promising therapeutic strategy for the treatment of glioma.

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Rottlerin inhibits the nuclear factor κB/Cyclin-D1 cascade in MCF-7 breast cancer cells

Cited by 41 publications

References 22 publications

Non-Selective Cation Channel-Mediated Ca<sup>2+</sup>-Entry and Activation of Ca<sup>2+</sup>/Calmodulin-Dependent Kinase II Contribute to G<sub>2</sub>/M Cell Cycle Arrest and Survival of Irradiated Leukemia Cells

Non-Selective Cation Channel-Mediated Ca<sup>2+</sup>-Entry and Activation of Ca<sup>2+</sup>/Calmodulin-Dependent Kinase II Contribute to G<sub>2</sub>/M Cell Cycle Arrest and Survival of Irradiated Leukemia Cells

Rottlerin exerts its anti-tumor activity through inhibition of Skp2 in breast cancer cells

Rottlerin inhibits cell growth and invasion via down-regulation of Cdc20 in glioma cells

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