SKI-606 Decreases Growth and Motility of Colorectal Cancer Cells by Preventing pp60(c-Src)–Dependent Tyrosine Phosphorylation of β-Catenin and Its Nuclear Signaling

Coluccia, Addolorata Maria Luce; Benati, Daniela; Dekhil, Hafedh; Filippo, Annamaria De; Lan, Cathy; Gambacorti‐Passerini, Carlo

doi:10.1158/0008-5472.can-05-2057

Cited by 109 publications

(86 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the association of AR and c-Src is also required for the AR-mediated activation of phosphatidylinositol 3-kinase-AKT signaling by direct interaction of AR and the p85␣ regulatory subunit of phosphatidylinositol 3-kinase (29,33). Therefore, therapeutic targeting of AR signaling might block genotropic signaling as AR antagonists do or inhibit nongenotropic signaling of AR, for example, with Src kinase inhibitors as their specificity and availability are improved (34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor

Teitell²,

Lawson

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

149

141

View full text Add to dashboard Cite

Classic work by Huggins and Hodges demonstrated that human prostate cancer regresses dramatically during antihormonal therapy but recurs frequently with androgen independence. Perturbations in the androgen receptor (AR) and PTEN-AKT signaling axes are significantly correlated with the progression of prostate cancer. Genetic alterations of the AR cause receptor hypersensitivity, promiscuity, and androgen-independent receptor transactivation. Prostate cancers maintain an elevated AKT activity through the loss of PTEN function or the establishment of autocrine signaling by growth factors and cytokines. We used an in vivo prostate regeneration system to investigate the biological potency of the potential crosstalk between these two signal transduction pathways. We demonstrate a direct synergy between AKT and AR signaling that is sufficient to initiate and progress naïve adult murine prostatic epithelium to frank carcinoma and override the effect of androgen ablation. Both genotropic and nongenotropic signals mediated by AR are essential for this synergistic effect. However, phosphorylation of AR by AKT at Ser-213 and Ser-791 is not critical for this synergy. These results suggest that more efficient therapeutics for advanced prostate cancer may need to target simultaneously AR signaling and AKT or the growth factor receptor tyrosine kinases that activate AKT.prostate regeneration ͉ tissue structure F undamental changes take place in androgen receptor (AR) signaling during prostate cancer progression (1, 2). AR signaling mediates cell differentiation and growth inhibition in the normal adult human and murine prostate (3-6). For example, AR can induce the expression of the luminal cell differentiation marker prostate-specific antigen (PSA) and the cell-cycle inhibitor p21. Transgenic mice harboring a prostatespecific AR transgene develop normal prostate tissues or show mild hyperplasia after a long latency period (7,8). However, cell autonomous androgen signals stimulate the proliferation of human or rodent AR-positive cancer cells (9). AR signaling also plays a critical role in the transition of prostate cancer from the androgen-dependent to -independent stage. Increased transcriptional level of AR mRNA has been demonstrated as the most common molecular determinant of resistance to antiandrogen therapy in a xenograft castration model (1).Loss of function of PTEN and activation of AKT are significantly correlated with the progression of prostate cancer (10). In vivo studies showed that murine prostatic intraepithelial neoplasia (mPIN) develops in transgenic mice expressing activated AKT1 specifically in the prostate (11). Previous in vitro studies using long-term passaged cancer cell lines have demonstrated that PTEN and AKT are, respectively, negative and positive modulators of AR transcriptional activity (12-15). Some papers have reported that AKT negatively regulates AR protein levels and transcriptional activity at the posttranscriptional (16) and posttranslational (17, 18) levels.We have modified and improved a p...

show abstract

Section: Discussionmentioning

confidence: 99%

Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor

Teitell²,

Lawson

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

149

141

View full text Add to dashboard Cite

show abstract

“…An increase of Src levels leads to a disruption of intercellular adhesion and Ecadherin dysfunction, while an inhibition of Src by small molecules has the opposite effect [353][354][355]. Hence, the Src kinase inhibitor bosutinib (SKI-606) ( Table 1) was shown to increase the membrane localization of -catenin and intercellular adhesion [356][357] and bosutinib has shown promising results in Phase I clinical trials in advanced solid tumors [358].…”

Section: Adherens Complexes In the Context Of -Catenin Signalingmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

View full text Add to dashboard Cite

Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

show abstract

“…Bosutinib is a dual inhibitor of both the ABL and Src kinases. [81][82][83] Bosutinib is more active than imatinib in vitro and has minimal activity against PDGFR or c-kit. 84,85 In preliminary data from the phase 2 portion of a phase 1/2 study investigating bosutinib in patients with CML-CP and resistance or intolerance to imatinib, 75 of 96 evaluable patients (78%) achieved a CHR, 47 of 106 (44%) achieved an MCyR, and 35 (33%) achieved a CCyR.…”

Section: Dasatinibmentioning

confidence: 99%

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Kantarjian

Cortés

Rosée

et al. 2010

Cancer

View full text Add to dashboard Cite

Identification of BCR‐ABL as the defining leukemogenic event in chronic myelogenous leukemia (CML) revolutionized the treatment of the disease. Imatinib, a potent BCR‐ABL inhibitor, is the standard of care for the first‐line treatment of patients with chronic‐phase CML because of its high long‐term response rates and favorable tolerability profile compared with previous standard therapies. However, resistance to imatinib develops in 2% to 4% of patients annually. For patients with acquired cytogenetic resistance to standard‐dose imatinib (400 mg daily), imatinib dose escalation (600‐800 mg daily) is an excellent first option for managing patients and achieving cytogenetic responses. However, for patients with primary resistance to imatinib, hematologic disease recurrence, or emergent BCR‐ABL kinase domain mutations, imatinib dose escalation may not be sufficient to control the disease. For these patients, the potent second‐generation tyrosine kinase inhibitors dasatinib and nilotinib are available. Both agents provide effective therapeutic options for patients with imatinib resistance or intolerance. For the current overview, the authors reviewed the data supporting the use of both dasatinib and nilotinib in imatinib‐resistant or imatinib‐intolerant patients, and they have highlighted the future of CML therapy. Overall, the article is intended to offer physicians a comprehensive review of the current literature and to provide data supporting various treatment options for patients with CML throughout the course of imatinib therapy and beyond. Cancer 2010. © 2010 American Cancer Society.

show abstract

SKI-606 Decreases Growth and Motility of Colorectal Cancer Cells by Preventing pp60(c-Src)–Dependent Tyrosine Phosphorylation of β-Catenin and Its Nuclear Signaling

Cited by 109 publications

References 44 publications

Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor

Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Contact Info

Product

Resources

About