Celecoxib induces anoikis in human colon carcinoma cells associated with the deregulation of focal adhesions and nuclear translocation of p130Cas

Casanova, Isolda; Parreño, Matilde; Farré, Lourdes; Guerrero, Sílvia; Céspedes, María Virtudes; Pavón, Miguel Ángel; Sancho, Ferrán; Marcuello, Eugenio; Trías, Manuel

doi:10.1002/ijc.21662

Cited by 35 publications

(44 citation statements)

References 57 publications

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“…This finding is consistent with our previous observation that p130Cas overexpression blocks the cytotoxic activity of celecoxib in colon carcinoma cells. 21 Similar observations have been reported in other malignant cells overexpressing p130Cas 9,32 or FAK 33 after different agent exposure. Our finding that most DLBCL patient samples showed expression of at least one of the studied FA proteins indicates that E7123 may be effective in patients.…”

Section: Discussionsupporting

confidence: 78%

“…21 We have also shown that E7123, a celecoxib derivative that does not inhibit COX-2, was more potent than celecoxib in inducing cell death by FA signaling inhibition in acute myeloid leukemia cells. 22 Our aim in this study was to evaluate whether E7123 was effective in DLBCL and determine its mechanism of action.…”

Section: Introductionmentioning

confidence: 80%

“…This finding is consistent with our previous observation that p130Cas overexpression blocks the cytotoxic activity of celecoxib in colon carcinoma cells. 21 E7123 induced caspase-independent cell death. This mechanism of cell death induction is essentially different from that of most current therapies for DLBCL.…”

Section: Discussionmentioning

confidence: 96%

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A novel inhibitor of focal adhesion signaling induces caspase-independent cell death in diffuse large B-cell lymphoma

Bosch

Dieguez-Gonzalez²,

Céspedes

et al. 2011

Blood

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Focal adhesion (FA) proteins have been associated with transformation, migration, metastasis, and poor outcome in many neoplasias. We previously showed that these proteins were inhibited by E7123, a new celecoxib derivative with antitumor activity, in acute myeloid leukemia. However, little is known about FAs in diffuse large B cell lymphoma (DLBCL). This paper aimed to determine whether E7123 was effective against DLBCL and whether FAs were involved in its action.We evaluated the cytotoxicity and mechanism of action of E7123 and celecoxib in DLBCL cell lines. We also assessed the E7123 in vivo activity in a DLBCL xenograft model and studied FA signaling in primary DLBCL patient samples. We found that E7123 showed higher antitumor effect than celecoxib against DLBCL cells. Its mechanism of action involved deregulation of FA, AKT, and Mcl-1 proteins, a pathway that is activated in some patient samples, apoptosis-inducing factor release and induction of caspase-independent cell death. Moreover, E7123 showed suppression of in vivo tumor growth. These findings indicate that E7123 is effective against DLBCL in vitro and in vivo, with a mechanism of action that differs from that of most current therapies for this malignancy. IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most frequent non-Hodgkin lymphoma subtype. Cure rates have increased in recent years with the addition of rituximab to the combination chemotherapy: cyclophosphamide, doxorubicin, vincristine, and prednisone. 1 However, a significant percentage of patients still relapse because lymphoma cells acquire resistance to therapy, which is associated with defective caspase-dependent apoptotic pathways. [2][3][4] Paradoxically, almost all cytotoxic drugs currently in clinical use for DLBCL induce caspase-dependent apoptosis. 5 Thus, the development of novel compounds with mechanisms of action able to induce caspase-independent cell death probably improves the therapeutic outcome in DLBCL, particularly in patients who relapse after front-line therapy.Focal adhesion (FA) complexes are structures that link the actin filaments of the cytoskeleton with the extracellular matrix. They are formed by transmembrane receptors (integrins) that activate various protein kinases, including the focal adhesion kinase (FAK) and Src family kinases. 6 Crk-associated substrate (CAS) family proteins act as docking proteins that associate with FAK and Src to generate specific cellular responses. 7 FA proteins have been related to transformation, 8 migration, 9 metastasis, 10 and poor outcome 11 in many solid tumors and in some hematologic malignancies. 12,13 However, there are limited data regarding the role of FA proteins in DLBCL. To our knowledge, only FAK and the Src-family protein LYN have been studied in DLBCL. FAK is expressed in 70% of DLBCLs 14 and LYN is constitutively phosphorylated and required for DLBCL growth, survival, and proliferation. 15,16 Other FA proteins, such as HEF1 or p130Cas from the CAS family, or PYK2 from the FAK family, play crucial roles ...

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 80%

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A novel inhibitor of focal adhesion signaling induces caspase-independent cell death in diffuse large B-cell lymphoma

Bosch

Dieguez-Gonzalez²,

Céspedes

et al. 2011

Blood

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“…4A, row 2). It has been reported that proteolysis of p130Cas is associated with the induction of apoptosis by different agents (etoposide, cisplatin, and celecoxib) and generates a 31-kDa fragment (15,16). This small fragment is translocated to the nucleus where it acts as a transcriptional repressor and leads to anoikis, a type of apoptosis caused by disruption of cell-matrix interactions (17).…”

Section: Resultsmentioning

confidence: 99%

A Selective Phosphatase of Regenerating Liver Phosphatase Inhibitor Suppresses Tumor Cell Anchorage-Independent Growth by a Novel Mechanism Involving p130Cas Cleavage

Daouti

Qian

et al. 2008

Cancer Research

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The phosphatase of regenerating liver (PRL) family, a unique class of oncogenic phosphatases, consists of three members: PRL-1, PRL-2, and PRL-3. Aberrant overexpression of PRL-3 has been found in multiple solid tumor types. Ectopic expression of PRLs in cells induces transformation, increases mobility and invasiveness, and forms experimental metastases in mice. We have now shown that small interfering RNAmediated depletion of PRL expression in cancer cells results in the down-regulation of p130Cas phosphorylation and expression and prevents tumor cell anchorage-independent growth in soft agar. We have also identified a small molecule, 7-amino-2-phenyl-5H-thieno[3,2-c]pyridin-4-one (thienopyridone), which potently and selectively inhibits all three PRLs but not other phosphatases in vitro. The thienopyridone showed significant inhibition of tumor cell anchorage-independent growth in soft agar, induction of the p130Cas cleavage, and anoikis, a type of apoptosis that can be induced by anticancer agents via disruption of cell-matrix interaction. Unlike etoposide, thienopyridone-induced p130Cas cleavage and apoptosis were not associated with increased levels of p53 and phospho-p53 (Ser 15 ), a hallmark of genotoxic druginduced p53 pathway activation. This is the first report of a potent selective PRL inhibitor that suppresses tumor cell three-dimensional growth by a novel mechanism involving p130Cas cleavage. This study reveals a new insight into the role of PRL-3 in priming tumor progression and shows that PRL may represent an attractive target for therapeutic intervention in cancer. [Cancer Res 2008;68(4):1162-9]

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“…In addition, it has been described that p130CAS cleavage may result from over-expression of the chemokine CXCL12 84 and also from the inhibition of activity of cyclooxygenase 2 (COX2), a key enzyme in prostaglandin synthesis that promotes tumour progression and angiogenesis 85 . Treatment of colon cancer cells with the COX2 inhibitor celecoxib induces proteolysis of p130CAS and nuclear translocation of the 31 kDa fragment, which leads to apoptosis 86 . Moreover, in a panel of human acute myeloid leukemia cell lines, the antitumour effect observed upon treatment with celecoxib is due to the inhibition of p130CAS signalling leading to apoptosis 87 .…”

Section: Apoptosismentioning

confidence: 99%

Integrin signalling adaptors: not only figurants in the cancer story

et al. 2010

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Current evidence highlights the ability of adaptor (or scaffold) proteins to create signalling platforms that drive cellular transformation upon integrin-dependent adhesion and growth factor receptor activation. The understanding of the biological effects regulated by these adaptors in tumours might be crucial for the identification of novel targets and the development of innovative therapeutic strategies for human cancer. In this review we will discuss the relevance of adaptor proteins in signalling originating from integrin-mediated cell-extracellular matrix (ECM) adhesion and growth factor stimulation within the context of cell transformation and tumour progression.Herein, we will specifically underline the contribution of p130CAS, NEDD9, CRK, and the IPP complex (ILK, PINCH and PARVIN) to cancer, along with the more recently identified p140CAP.

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Celecoxib induces anoikis in human colon carcinoma cells associated with the deregulation of focal adhesions and nuclear translocation of p130Cas

Cited by 35 publications

References 57 publications

A novel inhibitor of focal adhesion signaling induces caspase-independent cell death in diffuse large B-cell lymphoma

A novel inhibitor of focal adhesion signaling induces caspase-independent cell death in diffuse large B-cell lymphoma

A Selective Phosphatase of Regenerating Liver Phosphatase Inhibitor Suppresses Tumor Cell Anchorage-Independent Growth by a Novel Mechanism Involving p130Cas Cleavage

Integrin signalling adaptors: not only figurants in the cancer story

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