Alterations in levels of different protein kinase C isotypes and their influence on behavior of squamous cell carcinoma of the oral cavity: εPKC, a novel prognostic factor for relapse and survival

Martínez-Gimeno, Carlos; Diaz‐Meco, María T.; Domı́nguez, Isabel; Moscat, Jorge

doi:10.1002/hed.2880170609

Cited by 42 publications

(32 citation statements)

References 45 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: 48%

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: 48%

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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“…To date, there is only one publication of note focusing on the role of PKCs in HNSCC. In this study, PKCa, PKCh, PKCq, PKCg, and PKC~protein levels were shown to be elevated in the primary tumor tissue of oral cavity patients; however, only PKCq was found to be a prognostic marker in this small cohort of 29 patients, even better than the traditional gold standard of tumor-node-metastasis staging (11). Elevated PKCq was reported to be significantly associated with an increase in disease recurrence (P < 0.04) and a decrease in overall survival (P < 0.02).…”

Section: Resultsmentioning

confidence: 56%

“…Our laboratory reported that elevated PKCq is prognostic of lower overall and disease-free survival in patients with invasive breast cancer (10). Moreover, higher levels of PKCq were found to correlate with an increase in disease recurrence and a decrease in overall survival in HNSCC (11). In this study, we report that specific inhibition of PKCq is sufficient to dampen the invasive and motile phenotype of aggressive HNSCC.…”

Section: Introductionmentioning

confidence: 52%

Targeted Disruption of Protein Kinase Cε Reduces Cell Invasion and Motility through Inactivation of RhoA and RhoC GTPases in Head and Neck Squamous Cell Carcinoma

Pan

Bao²,

Teknos

et al. 2006

Cancer Research

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Over 70% of patients with head and neck squamous cell carcinoma (HNSCC) present with locoregionally advanced stage III and IV disease. In spite of aggressive therapy, locoregional disease recurs in 60% and metastatic disease develops in 15% to 25% of patients causing a major decline in quality and length of life. Therefore, there is a need to identify and understand genes that are responsible for inducing an aggressive HNSCC phenotype. Evidence has shown that protein kinase C (PKC) E is a transforming oncogene and may play a role in HNSCC progression. In this study, we determine the downstream signaling pathway mediated by PKCE to promote an aggressive HNSCC phenotype. RNA interference knockdown of PKCE in UMSCC11A and UMSCC36, two highly invasive and motile HNSCC cell lines with elevated endogenous PKCE levels, resulted in cells that were significantly less invasive and motile than the small interfering RNA-scrambled control transfectants; 51 F 5% (P < 0.006) and 49 F 3% (P < 0.010) inhibition in invasion and 69 F 1% (P < 0.0005) and 66 F 3% (P < 0.0001) inhibition in motility, respectively. PKCE-deficient UMSCC11A clones had reduced levels of active and serine-phosphorylated RhoA and RhoC. Moreover, constitutive active RhoA completely rescued the invasion and motility defect, whereas constitutive active RhoC completely rescued the invasion and partially rescued the motility defect of PKCE-deficient UMSCC11A clones. These results indicate that RhoA and RhoC are downstream of PKCE and critical for PKCE-mediated cell invasion and motility. Our study shows, for the first time, that PKCE is involved in a coordinated regulation of RhoA and RhoC activation, possibly through direct post-translational phosphorylation.

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“…PKC isoenzymes have been found to display variable expression profiles depending on specific cancer type. For example, PKCa and b has shown over-expressed in both high grade of prostate, gastrointestinal tract and head neck cancers (Koren et al, 2004;Lahn et al, 2004;Martinez-Gimeno et al, 1995). In contrast, hepatocellular and breast cancer display a downregulation of PKCa, and bladder cancer shows a down regulation of PKCb (Tsai et al, 2000;Kerfoot et al, 2004;Varga et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…As for PKC e and z, although their cellular function still obscure, their expressions have been reported in various cancers. PKCe has been shown upregulated in head neck, brain and prostate cancers (Xiao et al, 1994;Martinez-Gimeno et al, 1995;Sharif and Sharif, 1999;Koren et al, 2004), whereas downregulated in pancreatic cancer (Evans et al, 2003). PKCz have been shown upregulated in brain, liver and bladder cancers (Xiao et al, 1994;Tsai et al, 2000;Varga et al, 2004).…”

mentioning

confidence: 99%

hTERT phosphorylation by PKC is essential for telomerase holoprotein integrity and enzyme activity in head neck cancer cells

et al. 2006

Br J Cancer

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Telomerase activity is suppressed in normal somatic tissues but is activated in most cancer cells. We have previously found that all six telomerase subunit proteins, including hTERT and hsp90 are needed for full enzyme activity. Telomerase activity has been reported to be upregulated by protein kinase C (PKC), but the mechanism is not clear. In this study, we examined how PKC regulates telomerase activity in head and neck cancer cells. PKC inhibitor, bisindolylmaleimide I (BIS), inhibited telomerase activity but had no effect on the expressions of telomerase core subunits. RNA interference (RNAi) and in vitro phosphorylation studies revealed that PKC isoforms a, b, d, e, z specifically involved in telomerase regulation, and the phosphorylation target was on hTERT. Treatment with the hsp-90 inhibitor novobiocin dissociated hsp90 and hTERT as revealed by immunoprecipitation and immunoblot analysis and reduced telomerase activity. Treatment with the PKC activator SC-10 restored the association of hsp90 and hTERT and reactivate telomerase, suggesting that hTERT phosphorylation by PKC is essential for telomerase holoenzyme integrity and function. Analysis on clinical normal and tumour tissues reveal that the expressions of PKC a, b, d, e, z were higher in the tumour tissues, correlated with telomerase activity. Disruption of PKC phosphorylation by BIS significantly increased chemosensitivity to cisplatin. In conclusion, PKC isoenzymes a, b, d, e, z regulate telomerase activity in head and neck cancer cells by phosphorylating hTERT. This phosphorylation is essential for telomerase holoenzyme assembly, leading to telomerase activation and oncogenesis. Manipulation of telomerase activity by PKC inhibitors is worth exploring as an adjuvant therapeutic approach.

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Alterations in levels of different protein kinase C isotypes and their influence on behavior of squamous cell carcinoma of the oral cavity: εPKC, a novel prognostic factor for relapse and survival

Abstract: These results suggest participation of some PKC isotypes (alpha, beta, gamma, and zeta) in the genesis and behavior (epsilon) of oral cancers. Levels of epsilon PKC could be used as prognostic marker.

Cited by 42 publications

References 45 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

Targeted Disruption of Protein Kinase Cε Reduces Cell Invasion and Motility through Inactivation of RhoA and RhoC GTPases in Head and Neck Squamous Cell Carcinoma

hTERT phosphorylation by PKC is essential for telomerase holoprotein integrity and enzyme activity in head neck cancer cells

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