Cyr61 downmodulation potentiates the anticancer effects of zoledronic acid in androgen‐independent prostate cancer cells

Marra, Monica; Santini, Daniele; Meo, Giuseppina; Vincenzi, Bruno; Zappavigna, Silvia; Baldi, Alfonso; Rosołowski, Maciej; Tonini, Giuseppe; Loeffler, Markus; Lupu, Ruth; Addeo, Santolo Rosario; Abbruzzese, Alberto; Budillon, Alfredo; Caraglia, Michele

doi:10.1002/ijc.24648

Cited by 34 publications

(35 citation statements)

References 46 publications

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“…Very recently, Cbl -9h Cbl -9h Cbl -12h Cbl -12h A27/100 -NT A27-Cbl -4h A27-Cbl -9h A27/100 -NT A27/100 -Cbl-4h A27/100 -cos-4h A27/100 -cos-9h A27/100 -Cbl-9h A27/100 -Cbl-4h A27/100 -cos-4h downregulation of cyr61, which is shown to potentiate the anticancer activity of zoledronic acid in prostate cancer, 39 justifies its reduction in Cbl and Cbl cos cells. ARHGEF6, a Gcoupled receptor activated by phosphatidylinositol 3-kinase, modulates the cellular ROS level through Rac1.…”

Section: Discussionmentioning

confidence: 99%

Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Maiti

2009

Pharmacogenomics J

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Drug resistance in cancer cells involves complex molecular mechanisms and ovarian carcinoma cells become resistant to chlorambucil (Cbl) after continuous treatment. This drug-and ionizing radiation-resistant cells have lower level of endogenous ROS (reactive oxygen species) compared with sensitive cells. Elevation of the cellular ROS level by exogenous ROS generation increases the sensitivity of Cbl to resistant cells. In contrast, antioxidants prevent the sensitization of resistant cells to Cbl by H 2 O 2 , COS (chronic oxidative stress) or NOO À . The molecular mechanism of drug sensitivity with COS has been investigated by microarray gene expressions followed by gene network analysis and it reveals that a cdc42/rac1 guanine exchange factor, ARHGEF6, with p53 and DNA-Pkc (PRKDC) is central to induce apoptosis in Cbl cos (Cbl with COS) cells. mRNA and protein levels of major gene network pathway differ significantly in Cbl cos cells than in Cbltreated cells. Moreover, DNA-PKc physically interacts with ARHGEF6 and p53 mostly in the nucleus of Cbl-treated cells, whereas in Cbl cos -treated cells, its interactions are mostly in the cytoplasm. These results suggest that low doses of Cbl and very low doses of COS together kill Cbl-resistant ovarian carcinoma cells and ARHGEF6 signaling may have an instrumental role in induction of apoptosis in Cbl cos cells.

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Section: Discussionmentioning

confidence: 99%

Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Maiti

2009

Pharmacogenomics J

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“…However, lower concentrations were not applied in these experiments. 20 Treatment of PC-3 cells with ZA above 5 mM resulted in a significant reduction in invasion across bone-marrow endothelium. 30 Collectively, investigations have shown that ZA exerts anti-invasive properties on PC.…”

Section: Discussionmentioning

confidence: 95%

“…However, the anti-tumor potential of ZA was characterized recently by the decreased activation of the Akt-dependent pathways in a PC in vitro model, which supports our hypothesis. 20 Because downmodulation of cyclin E was seen in DU-145 and LNCaP, but not in PC-3 cells, this mechanism cannot be generalized. Rather, cyclin E might be sensitive to ZA treatment in particular tumor subpopulations.…”

Section: Discussionmentioning

confidence: 99%

Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro

Mani

Vallo

Barth

et al. 2012

Prostate Cancer Prostatic Dis

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BACKGROUND:The influence of the bisphosphonate zoledronic acid (ZA) on prostate cancer (PC) growth, adhesion and invasive behavior was investigated. METHODS: PC-3, DU-145 and LNCaP cells were treated with ZA, and tumor-cell growth was then investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, tumor-cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins, as well as migratory properties of the cells, was evaluated. Integrin b subtypes, integrin-dependent signaling, as well as cell-cycle regulating proteins, were analyzed by western blots. RESULTS: ZA dose-dependently reduced tumor-cell growth but did not impair tumor --endothelium and tumor --matrix interaction. However, ZA significantly inhibited tumor migration and invasive activity. Cyclin E was reduced by ZA in LNCaP and DU-145, and p21 was elevated in LNCaP cells. p27 was upregulated in all tumor cell lines, compared with the controls. ZA elevated b1-integrin in PC-3 and diminished b4-integrin in PC-3 and DU-145 cells. CONCLUSION: ZA inhibits PC growth and motility but does not influence the mechanical contact between tumor cells and the vascular wall.

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“…Expression of integrin is known to be induced through the activation of Akt and ERK pathway (Levy et al 2003). Collectively, these Cyr61 has been recognized as an effective molecule in inducing resistance of cancer cells to various chemotherapeutic drugs (Marra et al 2009). TRAIL has also been identified as a promising candidate for overcoming chemoresistance in tumor cells by activating the caspase cascade directly as well as its ability to induce a synergistic induction of apoptotic cell death when combined with other anticancer drugs (Ballestrero et al 2004).…”

Section: Discussionmentioning

confidence: 99%

“…In human prostate cancers, increased expression of Cyr61 has been also reported (Lv et al 2009). Cyr61 silencing enhances the anticancer effects of zoledronic acid through the inactivation of the Ras-dependent proliferation pathway in androgen-independent prostate cancer PC-3 and DU145 cells (Marra et al 2009). Cyr61 regulates Rac1 activation, and its downstream molecules are involved in growth, migration, and invasion of prostate cancer DU145 cells, whereas down-regulation of Cyr61 suppresses tumorigenicity and cell migration (Sun et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of cysteine-rich 61 inhibits proliferation, migration, and invasiveness of prostate carcinoma PC-3 cells

Lee

Jeong

et al. 2013

Animal Cells and Systems

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The overexpression of wild-type cysteine-rich 61 (Cyr61) is associated with the aggressiveness of cancer and poor prognosis in different human cancers. The aim of this study was to examine the expression of Cyr61 protein in prostate adenocarcinomas and to investigate the effects of inhibiting Cyr61 expression using small interfering RNA on the proliferation, migration, invasiveness, and sensitivity of prostate carcinoma PC-3 cells to TNF-related apoptosis-inducing ligand. Cell proliferation was measured by XTT assay. Colony formation assay, wound healing assay, and Matrigel invasion assay were also examined. Immunohistochemical staining of prostate tumor tissues showed that prostate carcinomas had significantly increased Cyr61 level compared with benign glands adjacent to carcinoma. siRNA-based knockdown of Cyr61 resulted in decreased cellular proliferation, clonogenicity, migration, and invasion. At the same time, Cyr61 silencing effectively reduced the levels of phosphorylated Akt and integrin-b 3 . Cyr61-specific siRNA combined with TRAIL increased the apoptosis of PC-3 cells and the cleavage of apoptosis hallmarkers such as PARP and caspase-3. Taken together, our data provide evidence that Cyr61 modulates integrinb 3 level as well as PI3-kinase/Akt activity through which Cyr61 may mediate tumorigenesis, and suggest the potential importance of Cyr61 targeting on enhancing the therapeutic efficacy of prostate cancer.

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Cyr61 downmodulation potentiates the anticancer effects of zoledronic acid in androgen‐independent prostate cancer cells

Cited by 34 publications

References 46 publications

Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Gene network analysis of oxidative stress-mediated drug sensitivity in resistant ovarian carcinoma cells

Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro

Knockdown of cysteine-rich 61 inhibits proliferation, migration, and invasiveness of prostate carcinoma PC-3 cells

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