Evidence that low doses of Taxol enhance the functional transactivatory properties of p53 on p21 waf promoter in MCF‐7 breast cancer cells

Panno, Maria Luisa; Giordano, Francesca; Mastroianni, Fabrizia; Morelli, Catia; Brunelli, Elvira; Palma, M. Grazia; Pellegrino, Michele; Aquila, Saveria; Miglietta, Antonella; Mauro, Loredana; Bonofiglio, Daniela; Andò, Sebastiano

doi:10.1016/j.febslet.2006.03.055

Cited by 25 publications

(28 citation statements)

References 30 publications

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“…In this context, p53 levels may depend on the PTX concentration used [31], so that low concentrations, like those used here, might reduce the functional transactivatory properties of p53, although this effect should be lower than that we observed in p53-deficient cells (cf. Figs.…”

Section: Discussioncontrasting

confidence: 47%

Apoptotic-like death occurs through a caspase-independent route in colon carcinoma cells undergoing mitotic catastrophe

2012

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Section: Discussioncontrasting

confidence: 47%

Apoptotic-like death occurs through a caspase-independent route in colon carcinoma cells undergoing mitotic catastrophe

2012

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“…Le François et al 34 reported that over expression of p16INK4A or CDK4 inhibition was associated with decreased levels of TS protein in colon cancer cells. On the other hand, Panno et al 35 reported that ''low dose'' paclitaxel treatment is able to activate p21 promoter via p53 in breast cancer cells. p21, an inhibitor of the cyclin/Cdk family, binds to and inhibits the activity of cyclin-CDK2 and -CDK4 complexes.…”

Section: Discussionmentioning

confidence: 99%

Low‐dose docetaxel enhances the sensitivity of S‐1 in a xenograft model of human castration resistant prostate cancer

Hasegawa¹,

Miyajima²,

Kosaka³

et al. 2011

Intl Journal of Cancer

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S-1 is a recently developed dihydropyrimidine dehydrogenase inhibitor fluoropyrimidine and has demonstrated high maximum plasma 5-Fluorouracil (5-FU) levels with mild toxicity, and an oral formulation has resulted in an improvement in patient quality of life. The aims of the present study were to determine the efficacy of S-1 or S-1 combined with docetaxel (DOC) using castration resistant prostate cancer (CRPC) cells and to explore their clinical potential for treating CRPC patients. LNCaP cells, androgen dependent prostate cancer (ADPC) cells and C4-2 cells, which are a CRPC subline of LNCaP cells, were used. Specimens obtained from ADPC and CRPC patients were also evaluated. The CRPC specimens and C4-2 cells exhibited significantly lower thymidylate synthase (TS) expression, a target of 5-FU, than the ADPC specimens and LNCaP cells. In vitro, C4-2 cells exhibited higher sensitivity to 5-FU than LNCaP cells. In C4-2 xenograft model, S-1 monotherapy suppressed tumor growth and low-dose DOC enhanced the anti-tumor effect of S-1. In vitro, low-dose DOC, which did not induce G2/M arrest, increased p53 and p21 and resulted in down-regulation of TS in C4-2 cells, and down-regulation of TS is considered to be responsible for the synergistic effect of S-1 in vivo. The present findings indicate that CRPC patients with androgen ablation may be good candidates for 5-FU based chemotherapy, and these regimens have attractive therapeutic potential for clinical practice, and they may have a significant impact on therapeutic options.

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“…wtCAV1 Regulates p53-dependent p21 Induction following Treatment with Paclitaxel-Low dose (ϳ10 nM) paclitaxel treatment can increase p21 synthesis through a p53-dependent pathway (34,35), and CAV1 and p53 can induce each other in fibroblasts (36). Inhibition of p53 expression with siRNA in MCF-7/wtCAV1 cells prevents paclitaxel-induced p21 protein expression (Fig.…”

Section: Increased Apoptosis In Mcf-7/wtcav1-expressing Cells In Respmentioning

confidence: 99%

Caveolin-1 Tyrosine Phosphorylation Enhances Paclitaxel-mediated Cytotoxicity

Shajahan

Wang

Decker

et al. 2007

Journal of Biological Chemistry

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Caveolin-1 (CAV1), a highly conserved membrane-associated protein, is a putative regulator of cellular transformation. CAV1 is localized in the plasmalemma, secretory vesicles, Golgi, mitochondria, and endoplasmic reticulum membrane and associates with the microtubule cytoskeleton. Taxanes such as paclitaxel (Taxol) are potent anti-tumor agents that repress the dynamic instability of microtubules and arrest cells in the G 2 /M phase. Src phosphorylation of Tyr-14 on CAV1 regulates its cellular localization and function. We report that phosphorylation of CAV1 on Tyr-14 regulates paclitaxel-mediated apoptosis in MCF-7 breast cancer cells. Befitting its role as a multitasking molecule, we show that CAV1 sensitizes cells to apoptosis by regulating cell cycle progression and activation of the apoptotic signaling molecules BCL2, p53, and p21. We demonstrate that phosphorylated CAV1 triggers apoptosis by inactivating BCL2 and increasing mitochondrial permeability more efficiently than non-phosphorylated CAV1. Furthermore, expression of p21, which correlates with taxane sensitivity, is regulated by CAV1 phosphorylation in a p53-dependent manner. Collectively, our findings underscore the importance of CAV1 phosphorylation in apoptosis and suggest that events that negate CAV1 tyrosine phosphorylation may contribute to anti-microtubule drug resistance. Caveolin-1 (CAV1)2 is a 21-24-kDa protein and the prototype of a family of integral membrane proteins that associate with specific cholesterol-and sphingolipid-rich domains to form the structural foundation of membrane invaginations called caveolae. Caveolae act as sites of signal transduction in various cell types (1). CAV1 is thought to regulate the activity of proteins such as Src kinases, epidermal growth factor tyrosine kinase, Her2/neu (ErbB2) kinase, ERK (extracellular signal-regulated kinase), H-Ras, endothelial nitric-oxide synthase, and G proteins (1, 2) involved in survival pathways. In human breast tumors, CAV1 levels inversely correlate with tumor size (3), and CAV1 expression reduces the growth of mouse mammary tumors and their spontaneous metastasis to lung and bone (4). However, in breast cancer cell culture models, CAV1 is downregulated in non-invasive human breast cancer cells but upregulated in cells with an invasive phenotype (5-7).Taxanes are potent anti-tumor agents that function by binding to the ␤ subunits of tubulin and repressing the dynamic instability of spindles (8, 9), activities that lead to cell cycle arrest in the G 2 /M phase (10). Taxanes such as paclitaxel (Taxol) or docetaxel (Taxotere) are routinely used in the firstline treatment of metastatic breast, lung, ovarian, and digestive cancers (11). In primary breast cancer, inclusion of taxane in adjuvant chemotherapy reduces the relative risk of recurrence and improves overall survival (12). Acquired resistance through cellular adaptations or mutations in neoplastic cells remains a major problem in chemotherapy. Although taxanes are substrates for ABC transporters, other resistance mechanis...

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Evidence that low doses of Taxol enhance the functional transactivatory properties of p53 on p21 waf promoter in MCF‐7 breast cancer cells

Cited by 25 publications

References 30 publications

Apoptotic-like death occurs through a caspase-independent route in colon carcinoma cells undergoing mitotic catastrophe

Apoptotic-like death occurs through a caspase-independent route in colon carcinoma cells undergoing mitotic catastrophe

Low‐dose docetaxel enhances the sensitivity of S‐1 in a xenograft model of human castration resistant prostate cancer

Caveolin-1 Tyrosine Phosphorylation Enhances Paclitaxel-mediated Cytotoxicity

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