The role of protein kinase C and novel phorbol ester receptors in tumor cell invasion and metastasis (Review).

Gómez, Daniel E.; Skilton, G; Alonso, Daniel F.; Kazanietz, Marcelo G.

doi:10.3892/or.6.6.1363

Cited by 34 publications

(46 citation statements)

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“…The coordinated release of intestinal peptides in response to extracellular mediators is essential for the regulation of intestinal digestion, secretion and motility; therefore, our results delineate critical signaling molecules that contribute to this important physiologic process. Interestingly, prominent regulators of PKD and NT secretion, namely PMA-sensitive PKCs (69) and RhoA (70) contribute to tumor progression. Since NT can stimulate proliferation of NTR positive tumors, it is interesting to speculate that pathways, such as RhoA and PKCs, may promote tumorigenesis through the dysregulated secretion of trophic factors such as NT.…”

Section: Discussionmentioning

confidence: 99%

The Role of Protein Kinase D in Neurotensin Secretion Mediated by Protein Kinase C-α/-δ and Rho/Rho Kinase

O’Connor

Hellmich

et al. 2004

Journal of Biological Chemistry

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Neurotensin (NT) is a gut peptide that plays an important role in gastrointestinal (GI) secretion, motility, and growth as well as the proliferation of NT receptor positive cancers. Secretion of NT is regulated by phorbol ester-sensitive protein kinase C (PKC) isoforms-␣ and -␦ and may involve protein kinase D (PKD). The purpose of our present study was: (i) to define the role of PKD in NT release from BON endocrine cells and (ii) to delineate the upstream signaling mechanisms mediating this effect. Here, we demonstrate that small interfering RNA (siRNA) targeted against PKD dramatically inhibited both basal and PMA-stimulated NT secretion; NT release is significantly increased by overexpression of PKD. PKC-␣ and -␦ siRNA attenuated PKD activity, whereas overexpression of PKC-␣ and -␦ enhanced PKD activity. Rho kinase (ROK) siRNA significantly inhibited NT secretion, whereas overexpression of ROK␣ effectively increased NT release. Rho protein inhibitor C3 dramatically inhibited both NT secretion and PKD activity. In conclusion, our results demonstrate that PKD activation plays a central role in NT peptide secretion; upstream regulators of PKD include PKC-␣ and -␦ and Rho/ROK. Importantly, our results identify novel signaling pathways, which culminate in gut peptide release.Regulatory hormones, localized to specialized endocrine cells in the small bowel, control numerous physiological functions of the gastrointestinal (GI) tract including secretion, motility, and mucosal growth (1). The gut peptide neurotensin (NT), 1 a tridecapeptide localized to enteroendocrine cells (N cells) of the distal small bowel (2, 3), facilitates fatty acid translocation (4), affects gut motility (5), and stimulates growth of normal gut mucosa (6, 7). In addition to its trophic effects on normal GI tissues, NT stimulates proliferation of certain pancreatic, colonic, and prostatic cancers bearing NT receptors (NTR) (8). Although the mechanisms for pancreatic hormone release have been well characterized (9), the signal transduction pathways regulating stimuli-induced gut hormone secretion are not entirely understood. One reason for this paucity in our understanding is the relative lack of useful in vitro models that recapitulate in vivo properties of intestinal endocrine cells.The BON endocrine cell line was established from a human pancreatic carcinoid tumor and characterized in our laboratory (10). These cells have served as an invaluable in vitro model for hormone secretion studies. Similar to the terminally differentiated N cell of the small bowel, BON cells express high levels of NT/neuromedin N mRNA, synthesize and secrete NT peptide, and process the NT/neuromedin N precursor protein in a fashion identical to that of the normal intestine (11). BON cells exhibit morphological and biochemical characteristics consistent with the enteroendocrine cell phenotype, including the presence of numerous dense core granules and the expression and secretion of chromogranin A and other peptides (e.g. pancreastatin) (10, 12, 13). Thus, the BON cel...

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Section: Discussionmentioning

confidence: 99%

The Role of Protein Kinase D in Neurotensin Secretion Mediated by Protein Kinase C-α/-δ and Rho/Rho Kinase

O’Connor

Hellmich

et al. 2004

Journal of Biological Chemistry

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“…To date, at least ten PKC isoforms have been identified, which differ in their expression patterns, substrate specificity, and response to extracellular stimuli (Clemens et al 1992, Lucas & Sanchez-Margalet 1995, Jaken 1996, Nishikawa et al 1997, Newton 2001. PKCs have been implicated in neoplastic transformation, the growth and metastasis of tumors, and response to therapy in a variety of tissues including breast, prostate, liver, colon, skin, stomach, and respiratory tract (Goodnight et al 1994, Kiley et al 1996, Cornford et al 1999, Gomez et al 1999, Spitaler et al 1999, Watters & Parsons 1999, Musashi et al 2000, Koivunen et al 2006. In endometrial cancers, the total PKC activity was significantly higher when compared with normal endometrial tissue (Fujimoto et al 1995) and differential overexpression of PKC isoforms has been linked to the proliferative potential of endometrial cancer cell lines and tumor pathogenesis (Gretz et al 1994, Bamberger et al 1996, 1997, Fujimoto et al 1996, Connor et al 1997.…”

Section: Introductionmentioning

confidence: 99%

Endometrial cancer cell survival and apoptosis is regulated by protein kinase C α and δ

Haughian

Jackson²,

Koterwas³

et al. 2006

Endocr Relat Cancer

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Endometrial cancer is the most common invasive gynecologic malignancy but the molecular mechanisms underlying its onset and progression are poorly understood. Paradoxically, endometrial tumors exhibit increased apoptosis, correlating with disease progression and poor patient prognosis. Endometrial tumors also show altered activity and expression of protein kinase C (PKC) isoforms, implicated in the regulation of programmed cell death; however, PKC modulation of apoptosis in endometrial cancer cells has not been investigated. We detected nine out of ten PKC isoforms in Ishikawa endometrial cancer cell lines, and demonstrated expression of both PKCa and d in human endometrial tumors. To determine the functional roles of PKCa and d in apoptosis in endometrial cancer, Ishikawa cells were treated with selective PKC inhibitors or adenoviral constructs encoding wild-type or isoform-specific, dominant-negative mutants. Apoptosis was assessed by DNA fragmentation and caspase-mediated poly-(ADP-ribose)-polymerase cleavage. The inhibition of PKCd suppressed etoposide-induced apoptosis, while overexpression of PKCd enhanced it. In contrast, inhibition of PKCa elevated basal levels of apoptosis and potentiated etoposide-induced cell death. Etoposide treatment also selectively activated PKCd, but resulted in both cytosolic translocation and decreased activity of PKCa. A fraction of PKCd also underwent caspase-dependent cleavage, in response to etoposide. Our results suggest that changes in apoptosis and PKC expression in endometrial cancer are mechanistically linked, such that PKCd is required for DNA damage-induced apoptosis, while PKCa mediates a survival response. Thus, PKCa and d expression and signaling may be important in endometrial tumorigenesis and could serve as potential prognostic indicators and/or novel targets for therapeutic intervention.

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“…Members of the PKC family are known to modulate cell migration (Gomez et al, 1999). We thus investigated their role in the effect of PEA-15 on astrocyte migration.…”

Section: A Member Of the Novel Pkc Family Mediates Pea-15 Inhibition mentioning

confidence: 99%

Phosphoprotein Enriched in Astrocytes-15 kDa Expression Inhibits Astrocyte Migration by a Protein Kinase Cδ-dependent Mechanism

Raffi

Beuvon

Iturrioz

et al. 2006

MBoC

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The role of protein kinase C and novel phorbol ester receptors in tumor cell invasion and metastasis (Review).

Cited by 34 publications

References 0 publications

The Role of Protein Kinase D in Neurotensin Secretion Mediated by Protein Kinase C-α/-δ and Rho/Rho Kinase

The Role of Protein Kinase D in Neurotensin Secretion Mediated by Protein Kinase C-α/-δ and Rho/Rho Kinase

Endometrial cancer cell survival and apoptosis is regulated by protein kinase C α and δ

Phosphoprotein Enriched in Astrocytes-15 kDa Expression Inhibits Astrocyte Migration by a Protein Kinase Cδ-dependent Mechanism

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