Gleevec Suppresses p63 Expression in Head and Neck Squamous Cell Carcinoma Despite p63 Activation by DNA‐Damaging Agents

Ongkeko, Weg M.; An, Yi; Chu, Theresa S.; Aguilera, Joseph; Dang, Christopher L; Wang‐Rodriguez, Jessica

doi:10.1097/01.mlg.0000225941.60901.0f

Cited by 13 publications

(15 citation statements)

References 17 publications

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“…It was even worse that some kinds of mutation can accelerate the progress of CML [37]. Meanwhile, it hadn’t been deeply deliberated over the adverse effects of TKI, especially imatinib, such as heart failure toxicity [38], acute renal failure [39], even the high possibility of progressing to other cancers with blocking the tumor suppressor p63 [40]. Taken together, a new therapeutic strategy that is independent of the kinase domain would be quite significant.…”

Section: Discussionmentioning

confidence: 99%

Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells

Huang

Gao

et al. 2017

IJMS

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The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which is expressed in the nucleus can induce apoptosis. Based on the hetero-dimerization of FKBP (the 12-kDa FK506- and rapamycin-binding protein) and FRB (the FKBP-rapamycin binding domain of the protein kinase, mTOR) mediated by AP21967, we constructed a nuclear transport system to induce cytoplasmic Bcr-Abl into nuclear. In this study, we reported the construction of the nuclear transport system, and we demonstrated that FN3R (three nuclear localization signals were fused to FRBT2098L with a FLAG tag), HF2S (two FKBP domains were in tandem and fused to the SH2 domain of Grb2 with an HA tag) and Bcr-Abl form a complexus upon AP21967. Bcr-Abl was imported into the nucleus successfully by the nuclear transport system. The nuclear transport system inhibited CML cell proliferation through mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) pathways mainly by HF2S. It was proven that nuclear located Bcr-Abl induced CML cell (including imatinib-resistant K562G01 cells) apoptosis by activation of p73 and its downstream molecules. In summary, our study provides a new targeted therapy for the CML patients even with Tyrosine Kinase Inhibitor (TKI)-resistance.

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Section: Discussionmentioning

confidence: 99%

Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells

Huang

Gao

et al. 2017

IJMS

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“…Phosphorylated ΔNp63 displayed a decreased ability to bind certain cell cycle arrest and apoptotic promoters, thus allowing rapid activation of the p53-dependent transcriptional apoptotic program 59. Interestingly, the Abl inhibitor, Gleevec was shown to reduce TAp63 expression in a dose-dependent manner in HNSCC cells thereby overriding its induction by DNA damaging agents 58,77…”

Section: Discussionmentioning

confidence: 99%

“…Apoptosis is a common feature of the cytotoxicity caused by DNA damaging anti-cancer agents 1,2,4,7,18,29,34,43,58,59,63,70. The overexpression of ΔNp63α was shown to an increase in cell proliferation, and enhanced tumor growth in vitro and in vivo and also to block UV-induced p53-dependent apoptosis in vivo 42,46.…”

Section: Introductionmentioning

confidence: 99%

ATM kinase is a master switch for the ΔNp63α phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon DNA damage

et al. 2008

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We previously found that the pro-apoptotic DNA damaging agent, cisplatin, mediated the proteasome-dependent degradation of DNp63a associated with its increased phosphorylated status. Since DNp63a usually plays an opposite role to p53 and TAp63 in human cancers, we tested the notion that phosphorylation events induced by DNA damage would affect the protein degradation of DNp63a in HNSCC cells upon cisplatin exposure. We found that DNp63a is phosphorylated in the time-dependent fashion at the following positions: S385, T397 and S466, which were surrounded by recognition motifs for ATM, CDK2 and p70s6K kinases, respectively. We showed that chemical agents or siRNA inhibiting the activity of ATM, CDK2 and p70s6K kinases blocked degradation of DNp63a in HNSCC cells after cisplatin exposure. Site-specific mutagenesis of DNp63a residues targeted for phosphorylation by ATM, CDK2 or p70s6k led to dramatic modulation of DNp63a degradation. Finally, we demonstrated that the DNp63a protein is a target for direct in vitro phosphorylation by ATM, CDK2 or p70s6K. Our results implicate specific kinases, and target phosphorylation sites in the degradation of DNp63a following DNA damage.

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“…Thus, the protective effects of imatinib seem to be of minor importance. Another reason might be the down-regulation of the proapoptotic gene p63 by imatinib (24). This tumor suppressor demonstrated a remarkable alteration of the apoptotic impact on cells by cisplatin (24).…”

Section: Discussionmentioning

confidence: 99%

“…Another reason might be the down-regulation of the proapoptotic gene p63 by imatinib (24). This tumor suppressor demonstrated a remarkable alteration of the apoptotic impact on cells by cisplatin (24). Besides p73, p63 is essential for the full apoptotic activity of the p53 family of tumor suppressors (25).…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC

Sauter¹

2011

Oncol Rep

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Abstract. Squamous cell carcinoma of the head and neck (HNSCC) is the most common neoplasm arising in the upper aerodigestive tract. Unfortunately, the survival for this type of cancer has not improved significantly in the past 25 years. To enhance the survival rate multimodal therapy regimens have been set up. In these regimens chemotherapy plays a pivotal role in the majority of advanced cases. Transmembrane proteintyrosine kinases (PTK) are fundamental elements of the signal transduction. In consequence, they might be promising targets for cancer therapy. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukemia. But imatinib also has an inhibitory impact on the PTK receptor c-kit and on its PTK activity. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). The ECM is altered by matrix metalloproteinases (MMP). In this study, we incubated different HNSCC cell lines with rising concentrations of imatinib and/or carboplatin. After an incubation time of up to 10 days, we evaluated c-kit, MMP-2 and MMP-14 by ELISA techniques and immunohistochemical methods. Especially the combination of 7.5 μmol carboplatin with 30 μmol imatinib resulted in a significant decrease in MMP-2 expression in all observed cell lines (p<0.05). We did not demonstrate a significant alteration in c-kit expression by imatinib and carboplatin. We observed an increase in apoptosis in HNSCC cells by the combination of the two observed chemotherapeutic drugs. In all cell lines tested, expression of c-kit and MMP could be demonstrated. Our results indicate that MMP-2 expression was suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially one keeping in mind the moderate toxicity of imatinib.

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Gleevec Suppresses p63 Expression in Head and Neck Squamous Cell Carcinoma Despite p63 Activation by DNA‐Damaging Agents

Cited by 13 publications

References 17 publications

Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells

Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells

ATM kinase is a master switch for the ΔNp63α phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon DNA damage

Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC

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Gleevec Suppresses p63 Expression in Head and Neck Squamous Cell Carcinoma Despite p63 Activation by DNA‐Damaging Agents

Cited by 13 publications

References 17 publications

Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells

Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells

ATM kinase is a master switch for the &Delta;Np63&alpha; phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon DNA damage

Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC

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ATM kinase is a master switch for the ΔNp63α phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon DNA damage