Down‐regulation of protein kinase C‐α detected in human colorectal cancer

Suga, Kenji; Sugimoto, Isamu; Ito, Hisao; Hashimoto, Eikichi

doi:10.1080/15216549800201552

Cited by 24 publications

(21 citation statements)

References 8 publications

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“…Our data about up-regulation of PKCi/k in Apc Min/+ tumors are not confirmed by Paoni and Leclerc (whereas PKCL/E was not tested by Klein et al), but they support results obtained from patients and other animal models (21). For PKCf, the previous studies (with the exception of Leclerc) agree with us on a down-regulation of this gene in tumor tissue, which again is consistent with patient data (40) and other animal models (37).…”

Section: Pkcasupporting

confidence: 82%

Protein Kinase C α but not PKCζ Suppresses Intestinal Tumor Formation in ApcMin/+ Mice

2006

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Members of the protein kinase C (PKC) family of serine/ threonine kinases play key regulatory roles in numerous cellular processes, including differentiation and proliferation. Of the 11 mammalian PKC isoforms known, several have been implicated in tumor development and progression. However, in most cases, isotype specificity is poorly defined, and even contrary functions for a single PKC have been reported mostly because appropriate molecular and genetic tools were missing to specifically assess the contribution of single PKC isoforms in vivo. In this report, we therefore used PKC genetic targeting to study the role of PKCA and PKCZ in colorectal cancer. Both isoforms were found to be strongly down-regulated in intestinal tumors of Apc Min/+ mice. A deletion of PKCz did not affect tumorigenesis in this animal model. In contrast, PKCadeficient Apc Min/+ mice developed more aggressive tumors and died significantly earlier than their PKCA-proficient littermates. Even without an additional Apc mutation, PKCa knockout mice showed an elevated tendency to develop spontaneous intestinal tumors. Transcriptional profiling revealed a role for this kinase in regulating epidermal growth factor receptor (EGFR) signaling and proposed a synergistic mechanism for EGFR/activator protein and WNT/APC pathways in mediating intestinal tumor development.

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Section: Pkcasupporting

confidence: 82%

Protein Kinase C α but not PKCζ Suppresses Intestinal Tumor Formation in ApcMin/+ Mice

2006

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“…Consistent with this supposition, the down-regulation of PKC-ct was observed in human colorectal cancer in our laboratory (16). Based on the previous results (l, 8), the molecular mechanism of PKC down-regulation seems to be composed of at least two processes, namely the binding of PKC to plasma membrane and the subsequent formation of an activated conformation on the membrane, and proteolytic degradation of PKC by some endogenous protease.…”

Section: Modulation By Diacylglycerol Of Pkc-ct Binding To Plasma Memsupporting

confidence: 74%

Possible role of alteration in pH, but not in ionic strength, in the modulation of Ca2 ‐dependent and diacylglycerol‐induced association of protein kinase C‐α with plasma membrane

1998

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Summary: in an attempt to elucidate the mechanism of the membrane binding of protein kinase C-ct (PKC-c0, effects of pH and ionic strength were examined on Ca2+-dependent and diacylglycerol-induced association of this PKC with rat liver plasma membrane. In the absence of diacylglycerol, the membrane-bound PKC-ct increased according to the changes in pH from 6 to 8. However, these reactions were not seriously influenced by alterations in ionic strength (0-240 mM NaCl). In the presence of diacylglycerol, this pH-modulated binding of PKC-ct to plasma membrane was more effective under lower Ca 2+ concentration at pH 8. These results suggest that alkaline pH conditions seem to be important for preferable association of PKC-ct with plasma membrane.

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“…Overexpression of PKCßII in colonic epithelium seems to results in hyperproliferation and an increased susceptibility to carcinogenesis with an early increase in carcinogenesis, whereas PKC was downregulated in colonic tumors (43,44). Data from Orchel et al (45) have shown that differentiation of Caco-2 cells by butyrate treatment is dependent on PKC and c-Jun N-terminal kinase (JNK) activity.…”

Section: Discussionmentioning

confidence: 99%

Butyrate-induced alterations of phosphoinositide metabolism, protein kinase C activity and reduced CD44 variant expression in HT-29 colon cancer cells

Kopp¹,

Fichter²,

Assert³

et al. 2009

Int J Mol Med

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Abstract. Initiation of cell growth and neoplastic transformation frequently involves activation of growth factor receptor-coupled tyrosine kinases and stimulation of the phosphoinositide second messenger system. Altered expression of CD44 variants was reported in several malignant tumor types with possible implications for tumor progression and prognosis. CD44 variant expression was reported to be associated with second messenger activation and differentiation. We therefore investigated the effects of butyrateinduced short-term differentiation on phosphoinositide signaling, phospholipase C and protein kinase C activity and alteration of CD44 variant expression in human HT-29 colon carcinoma cells. HT-29 cells were cultured with sodium butyrate for 6 days. Phosphoinositide turnover was measured by [32 P]orthophosphate incorporation and phospholipase C activity by determination of the release of [ 3 H]inositolphosphates from [ 3 H]myoinositol prelabeled cells. Protein kinase C activity was determined by histone III-S phosphorylation, PKC subtype expression by RNase protection analysis, and CD44 variant expression was determined by RT-PCR using variant-specific primers. Treatment of HT-29 human colon carcinoma cells with sodium butyrate caused a dose-dependent inhibition of cell proliferation (IC 50 , 2.5 mM) with morphologic signs of an enterocytic differentiation following 6 days of treatment. The phosphoinositide turnover as determined by 32 P-incorporation under non-equilibrium conditions showed a 30-40% inhibition of labeled phosphoinositides and phosphatidic acid and a dose-dependent inhibition of cholinergically stimulated phospholipase C activity as a secondary event following butyrate-induced enterocytic differentiation. However, long-term incubation of HT-29 cells with phorbol ester or an inhibitor of classical and novel PKC subtypes did not affect cell proliferation. In butyrate-treated HT-29 cells activation of calcium-dependent protein kinase C by cholinergic stimulation or phorbolester treatment induced an increase in membrane-bound cPKC activity, while expression of distinct high-molecular CD44 variant transcripts v3 (670 bp), v5 (940 bp) and v8 (535 bp) were drastically reduced after butyrate pretreatment. Enterocytic differentiation of HT-29 colon carcinoma cells seems to be associated with alterations in phosphoinositide resynthesis, phospholipase C activity and ligand/receptorinduced PKC translocation. The observed reduction of distinct high-molecular CD44v3, v5 and v8 variants following butyrate-induced differentiation indicates an association of specific CD44 variant expression with the malignant phenotype of HT-29 colon cancer cells, thus being possible targets for new diagnostic and therapeutic strategies.

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Down‐regulation of protein kinase C‐α detected in human colorectal cancer

Cited by 24 publications

References 8 publications

Protein Kinase C α but not PKCζ Suppresses Intestinal Tumor Formation in ApcMin/+ Mice

Protein Kinase C α but not PKCζ Suppresses Intestinal Tumor Formation in ApcMin/+ Mice

Possible role of alteration in pH, but not in ionic strength, in the modulation of Ca2 ‐dependent and diacylglycerol‐induced association of protein kinase C‐α with plasma membrane

Butyrate-induced alterations of phosphoinositide metabolism, protein kinase C activity and reduced CD44 variant expression in HT-29 colon cancer cells

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