Protein kinase C activation by phorbol ester increases in vitro invasion through regulation of matrix metalloproteinases/tissue inhibitors of metalloproteinases system in D54 human glioblastoma cells

Park, Myungjin; Park, In-Chul; Hur, Jin-Heang; Rhee, Chang-Hun; Choe, Taeboo; Yi, Dong-Hee; Hong, Seok‐Il; Lee, Seung‐Hoon

doi:10.1016/s0304-3940(00)01358-6

Cited by 56 publications

(35 citation statements)

References 13 publications

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“…All these effects of PMA were reversed by the addition of the PKC inhibitor Go 6983 [169]. Comparable effects were reported upon downregulation of PKC by bryostatin 1, which led to the stimulation of TIMP-1 activity, as well as a reduction in MMP production [166].…”

Section: Pkc and Cell Invasionmentioning

confidence: 88%

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Targeting Protein Kinase C: New Therapeutic Opportunities Against High-Grade Malignant Gliomas?

et al. 2002

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A large body of evidence suggests that the abnormal phenotype of neoplastic astrocytes, including their excessive proliferation rate and high propensity to invade surrounding tissues, results from mutations in critical genes involved in key cellular events. These genetic alterations can affect cell-surface-associated receptors, elements of signaling pathways, or components of the cell cycle clock, conferring a gain or a loss of relevant metabolic functions of the cells. The understanding of such phenomena may allow the development of more efficacious forms of cancer treatment. Examples are therapies specifically directed against overexpressed epidermal growth factor receptor, hyperactive Ras, excessively stimulated Raf-1, overproduced ornithine decarboxylase, or aberrantly activated cyclindependent kinases. The applicability of some of these approaches is now being assessed in patients suffering from primary malignant central nervous system tumors that are not amenable to current therapeutic modalities. Another potentially useful therapeutic strategy against such tumors involves the inhibition of hyperactive or overexpressed protein kinase C (PKC). This strategy is justified by the decrease in cell proliferation and invasion following inhibition of the activity of this enzyme observed in preclinical glioma models. Thus, interference with PKC activity may represent a novel form of experimental cancer treatment that may simultaneously restrain the hyperproliferative state and the invasive capacity of high-grade malignant gliomas without inducing the expected toxicity of classical cytotoxic agents. Of note, the experimental use of PKC-inhibiting agents in patients with refractory high-grade malignant gliomas has indeed led to some clinical responses. The present paper reviews the current status of the biochemistry and molecular biology of PKC, as well as the possibilities for developing novel anti-PKC-based therapies for central nervous system malignancies. The

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Section: Pkc and Cell Invasionmentioning

confidence: 88%

“…Moreover, treatment of cultured human glioblastoma cells with PMA induced the secretion of MMP-9, led to the activation of MMP-2, downregulated TIMP-1 and TIMP-2 secretion, and increased MT1-MMP on the cell surface [169]. All these effects of PMA were reversed by the addition of the PKC inhibitor Go 6983 [169].…”

Section: Pkc and Cell Invasionmentioning

confidence: 99%

Targeting Protein Kinase C: New Therapeutic Opportunities Against High-Grade Malignant Gliomas?

et al. 2002

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“…These results suggest that PKC-mediated elevation in MMP-9 expression and activity increase transwell invasion in HP75 cells. PKC has been implicated in the invasion of a number of tumor cells, including astrocytomas, 44 urinary bladder carcinomas, 45 colon carcinomas, 46 and breast cancers. 47 Initial observation of a point mutation of PKC-␣ and a higher overall PKC activity and expression in invasive PAs reported by Alvaro and colleagues 4,5 was not confirmed by others.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-9 Is Differentially Expressed in Nonfunctioning Invasive and Noninvasive Pituitary Adenomas and Increases Invasion in Human Pituitary Adenoma Cell Line

Hussaini

Trotter

Zhao

et al. 2007

The American Journal of Pathology

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The complete resection of pituitary adenomas (PAs) is unlikely when there is an extensive local dural invasion and given that the molecular mechanisms remain primarily unknown. DNA microarray analysis was performed to identify differentially expressed genes between nonfunctioning invasive and noninvasive PAs. Gene clustering revealed a robust eightfold increase in matrix metalloproteinase (MMP)-9 expression in surgically resected human invasive PAs and in the (nonfunctioning) HP75 human pituitary tumorderived cell line treated with phorbol-12-myristate-13-acetate; these results were confirmed by real-time polymerase chain reaction, gelatin zymography, reverse transcriptase-polymerase chain reaction, Western blot, immunohistochemistry, and Northern blot analyses. The activation of protein kinase C (PKC) increased both MMP-9 activity and expression, which were blocked by some PKC inhibitors (Gö6976, bisindolylmaleimide, and Rottlerin), PKC-␣, and PKC-␦ small interfering (si)RNAs but not by hispidin (PKC-␤ inhibitor). In a transmembrane invasion assay, phorbol-12-myristate-13-acetate (100 nmol/L) increased the number of invaded HP75 cells, a process that was attenuated by PKC inhibitors, MMP-9 antibody, PKC-␣ siRNA, or PKC-␦ siRNA. These results demonstrate that MMP-9 and PKC-␣ or PKC-␦ may provide putative therapeutic targets for the control of PA dural invasion. (Am J

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“…For example, it has been shown that phorbol 12-myristate 13-acetate (PMA), a PKC activator, induces MMP-2 activation and promotes invasiveness of glioblastoma cells in vitro; blocking PKC activity by selective PKC inhibitors eliminates PMA-induced MMP-2 activation and cell invasion. 76,77 On the other hand, Chang et al 78 demonstrate that PKC inhibitors (H7 and Go6976) inhibit MMP-2 production in cultured human pulp cells, suggesting PKCs are involved in the regulation of MMP-2 expression. In contrast, Yeung and Hurta 79 report that PMA downregulates MMP-2 mRNA in the H-ras-transformed mouse fibroblast cell line.…”

Section: Discussionmentioning

confidence: 99%

Ethanol‐induced in vitro invasion of breast cancer cells: The contribution of MMP‐2 by fibroblasts

Aye

Lin

et al. 2004

Intl Journal of Cancer

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Ethanol is a tumor promoter and may promote metastasis of breast cancer. However, the underlying cellular/molecular mechanisms remain unknown. Overexpression and high activity of matrix metalloproteinase-2 (MMP-2) are frequently associated with metastatic breast cancers and serve as a prognostic indicator of clinical outcome. MMP-2 is predominantly expressed in stromal fibroblasts and plays a pivotal role in regulating the invasive behavior of breast tumor cells. We hypothesized that ethanol may enhance the invasion of breast tumor cells by modulating the activity of fibroblastic MMP-2. With in vitro models (HS68 and CCD1056SK human fibroblasts), we showed that ethanol at physiologically relevant concentrations (50 -200 mg/dl) activated MMP-2; conversely, at a higher concentration (400 mg/dl), it inhibited the MMP-2 activity. Consistently, conditioned medium collected from ethanol ( Key words: alcohol; ErbB; metastasis; proteinases; signal transductionBreast cancer is a leading cause of morbidity and mortality in women. 1 The endogenous and environmental factors that contribute to its etiology remain elusive. Despite being responsive to hormonal manipulation and chemotherapy, relapse after treatment is common, particularly in patients presenting with metastatic disease. 2 The metastatic process involves the degradation of different macromolecular components of the extracellular matrix (ECM) and basement membranes and is regulated by intrinsic properties of the tumor cells as well as microenvironmental factors. Alcohol is a tumor promoter; there is a positive correlation between alcohol intake and the risk of several human cancers, including mouth/oropharyngeal cancer, oesophageal cancer, liver cancer and breast cancer. [3][4][5][6][7][8][9][10][11] Epidemiologic studies indicate that alcohol consumption is associated with advanced and invasive breast tumors, [12][13][14] suggesting that alcohol may enhance tumor development and metastasis. These epidemiologic results are supported by experimental studies using animal models and cell culture systems, which show that ethanol promotes mammary tumorigenesis and stimulates proliferation as well as invasion of breast cancer cells. [15][16][17][18][19][20][21] The molecular mechanisms underlying ethanol action, however, remain to be determined.Abnormal communication between the mammary epithelium and stromal cells promotes tumorigenesis and development of breast carcinomas. 22 Cancer-stroma interaction is mediated at least in part through the matrix metalloproteinases (MMPs). MMPs are a family of zinc-dependent endopeptidases that collectively are capable of degrading all components of the ECM. MMPs have been implicated in normal matrix remodeling events such as development of the mammary gland 23 and in pathologic conditions, including tumor invasion and metastasis. 24 Coupled with their function in metastasis, the MMPs also have a role in carcinogenesis. 25,26 High levels of MMP-2 and MMP-9 have been found to correlate with enhanced metastasis and poor prognosis in ...

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Protein kinase C activation by phorbol ester increases in vitro invasion through regulation of matrix metalloproteinases/tissue inhibitors of metalloproteinases system in D54 human glioblastoma cells

Cited by 56 publications

References 13 publications

Targeting Protein Kinase C: New Therapeutic Opportunities Against High-Grade Malignant Gliomas?

Targeting Protein Kinase C: New Therapeutic Opportunities Against High-Grade Malignant Gliomas?

Matrix Metalloproteinase-9 Is Differentially Expressed in Nonfunctioning Invasive and Noninvasive Pituitary Adenomas and Increases Invasion in Human Pituitary Adenoma Cell Line

Ethanol‐induced in vitro invasion of breast cancer cells: The contribution of MMP‐2 by fibroblasts

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