Akt, protein kinase C, and mitogen-activated protein kinase phosphorylation status in head and neck squamous cell carcinoma

Tosi, Lara; Rinaldi, Eliana; Farina, Antonio; Pastore, Antonio Luigi; Pelucchi, Stefano; Cassano, Lazzaro; Evangelisti, R.; Carinci, Paolo; Volinia, Stefano

doi:10.1002/hed.20120

Cited by 16 publications

(16 citation statements)

References 32 publications

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“…Although similar expression of PKCs (a, y, q, D, and~) in normal human keratinocytes was observed (16), different expression patterns have also been reported (17). There is limited data available about PKC expression in SCCHN, and the results are conflicting (18,19). Our study would suggest that the novel isoforms (y, q, and u) are highly expressed in SCCHN cell lines.…”

Section: Discussionsupporting

confidence: 46%

Protein Kinase Cζ Mediates Epidermal Growth Factor–Induced Growth of Head and Neck Tumor Cells by Regulating Mitogen-Activated Protein Kinase

Cohen¹,

Lingen

Zhu

et al. 2006

Cancer Research

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Protein kinase C (PKC) Z has been implicated as a mediator of epidermal growth factor (EGF) receptor (EGFR) signaling in certain cell types. Because EGFR is ubiquitously expressed in squamous cell carcinomas of the head and neck (SCCHN) and plays a key role in tumor progression, we determined whether PKCZ is required for tumor cell proliferation and viability. Examination of total and phosphorylated PKCZ expression in normal oral mucosa, dysplasia, and carcinoma as well as SCCHN tumor cell lines revealed a significant increase in activated PKCZ expression from normal to malignant tissue. PKCZ activity is required for EGF-induced extracellular signalregulated kinase (ERK) activation in both normal human adult epidermal keratinocytes and five of seven SCCHN cell lines. SCCHN cells express constitutively activated EGFR family receptors, and inhibition of either EGFR or mitogenactivated protein kinase (MAPK) activity suppressed DNA synthesis. Consistent with this observation, inhibition of PKCZ using either kinase-dead PKCZ mutant or peptide inhibitor suppressed autocrine and EGF-induced DNA synthesis. Finally, PKCZ inhibition enhanced the effects of both MAPK/ERK kinase (U0126) and broad spectrum PKC inhibitor (chelerythrine chloride) and decreased cell proliferation in SCCHN cell lines. The results indicate that (a) PKCZ is associated with SCCHN progression, (b) PKCZ mediates EGF-stimulated MAPK activation in keratinocytes and SCCHN cell lines, (c) PKCZ mediates EGFR and MAPK-dependent proliferation in SCCHN cell lines; and (d) PKCZ inhibitors function additively with other inhibitors that target similar or complementary signaling pathways. (Cancer Res 2006; 66(12): 6296-303)

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Section: Discussionsupporting

confidence: 46%

Protein Kinase Cζ Mediates Epidermal Growth Factor–Induced Growth of Head and Neck Tumor Cells by Regulating Mitogen-Activated Protein Kinase

Cohen¹,

Lingen

Zhu

et al. 2006

Cancer Research

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“…8,16 Thus, the phosphatidylinositol 3-kinase (PI3K)/AKT pathway is considered to be a predominant target of perifosine action. 8,17 The PI3-kinase/AKT/PTEN pathway is frequently dysregulated in SCCHN and AKT activation may correlate with patient outcome, [18][19][20][21] which make perifosine an attractive agent for study in SCCHN.…”

Section: Introductionmentioning

confidence: 99%

A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer

Argiris

Cohen

Karrison

et al. 2006

Cancer Biology & Therapy

109

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Background: Novel, effective therapies are warranted in the management of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Perifosine is an oral alkylphospholipid that inhibits AKT phosphorylation and has shown preclinical antitumor activity in head and neck cancer cell lines and xenografts.Patients And Methods: We conducted a phase II trial of perifosine in patients with incurable, recurrent or metastatic SCCHN. Previous therapy for recurrent or metastatic disease was limited to no more than one prior chemotherapy and one prior targeted/ biologic agent regimen. Patients had to have measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate laboratory parameters. Perifosine was given as a loading dose of 150 mg every 6 hours × 6 doses orally in the first two days, with antiemetic prophylaxis, followed by 100 mg/day orally without interruption. Administration via gastrostomy tube was allowed. Tumor response was assessed every two cycles (eight weeks). Biomarkers in pathways potentially affected by perifosine, including AKT, P-AKT, P38, p53 and p21 were measured on tumor tissue by immunohistochemistry by manual and automated methods.Results: Nineteen patients were enrolled. No objective responses were observed. One patient had stable disease as best response and 18 patients progressed at first evaluation. The median overall survival time was 5.5 months and the median progression-free survival time was 1.7 months. The most frequent toxicities were gastrointestinal (constipation, nausea, vomiting) and fatigue. One patient developed grade 4 anorexia. Although the sample size was small, a significant correlation was detected between high expression of P38 and AKT in baseline tumor tissue and better survival.Conclusions: Perifosine in the doses and schedule used lacks single-agent activity in SCCHN. Our data do not justify further investigation of perifosine as a single agent in SCCHN.

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“…Also, Akt/PKB has been implicated as a signaling intermediate upstream of survival genes, dependent on the transcription factor NF-kB, which induces cellular inhibitors of apoptosis (Beraud et al, 1999;Kane et al, 2001). Furthermore, activation of Akt/PKB has been shown to be important in progression of SCCHN (Tosi et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Chemokine receptor 7 activates phosphoinositide-3 kinase-mediated invasive and prosurvival pathways in head and neck cancer cells independent of EGFR

et al. 2005

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Chemokine receptor 7 (CCR7) upregulation, which mediates immune cell survival and migration to lymph nodes, has recently been associated with nodal metastasis of squamous cell carcinoma of the head and neck (SCCHN). However, the mechanism of CCR7 in tumor progression, its downstream signaling mediators, and interactions with other pathways contributing to metastasis of SCCHN have not been determined. We hypothesized that inflammatory chemokine-mediated signals could also promote tumor proliferation and mitogenic effects. Functional assays showed that chemotaxis and invasion of metastatic SCCHN cells were dependent on phosphoinositide-3 kinase (PI3K) and its substrate, activated phospholipase Cc-1. In addition, treatment of CCR7 þ metastatic SCCHN cells with CCL19 (MIP-3b) showed rapid activation of the prosurvival, PI3K/Akt pathway. Transactivation of EGFR-mediated and mitogen-activated protein kinase signaling pathways, which can promote migration and survival in parallel, did not appear to contribute to the functional or biochemical effects of CCR7 stimulation. Thus, proinflammatory chemokine signals that mediate activation, trafficking and survival of tumor-infiltrating immune cells in the tumor microenvironment actually appear to induce signals for progression of cancer cells. The CCR7-mediated pathway in metastatic SCCHN cells functions independently of EGFR signal transduction and therefore may represent an additional target for therapeutic intervention to prevent tumor progression and metastasis.

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Akt, protein kinase C, and mitogen-activated protein kinase phosphorylation status in head and neck squamous cell carcinoma

Abstract: This novel evidence documents important changes in the phosphorylation program during cancer progression of HNSCC.

Cited by 16 publications

References 32 publications

Protein Kinase Cζ Mediates Epidermal Growth Factor–Induced Growth of Head and Neck Tumor Cells by Regulating Mitogen-Activated Protein Kinase

Protein Kinase Cζ Mediates Epidermal Growth Factor–Induced Growth of Head and Neck Tumor Cells by Regulating Mitogen-Activated Protein Kinase

A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer

Chemokine receptor 7 activates phosphoinositide-3 kinase-mediated invasive and prosurvival pathways in head and neck cancer cells independent of EGFR

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