A protein kinase C inhibitor induces phenotypic reversion of ras -transformed pancreatic cancer cells and cooperatively blocks tumor cell proliferation with an anti- ras peptide

Way, Denise; Smith, Steven J.; Sivendran, Sharmila; Chie, Lyndon; Kanovsky, Mecheal; Brandt‐Rauf, Paul W.; Chung, Denise; Michl, Josef; Pincus, Matthew R.

doi:10.1007/s00280-002-0432-8

Cited by 8 publications

(6 citation statements)

References 9 publications

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“…In addition, PKCα has been attributed to induce drug resistance of pancreatic cancer cells [9]. In line with this, treatment with staurosporine blocked pancreatic cancer cell proliferation and reverted Ras-mediated transformation [10]. However, there are other reports showing that activation of PKCα inhibits the proliferation of pancreatic cancer cell lines [11] and increases the expression of pro-apoptotic proteins [12].…”

Section: Approaches To Target Classical Protein Kinase C (Cpkc) Subtymentioning

confidence: 99%

Targeting protein kinase C subtypes in pancreatic cancer

Störz

2015

Expert Review of Anticancer Therapy

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Summary In preclinical studies protein kinase C (PKC) enzymes have been implicated in regulating many aspects of pancreatic cancer development and progression. However, clinical phase I or phase II trials with compounds targeting classical PKC isoforms were not successful. Recent studies implicate that mainly atypical and novel PKC enzymes regulate oncogenic signaling pathways in pancreatic cancer. Members of these two subgroups converge signaling induced by mutant Kras, growth factors and inflammatory cytokines. Different approaches for development of inhibitors for aPKC and nPKC have been described; and new compounds include allosteric inhibitors and inhibitors that block ATP binding.

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Section: Approaches To Target Classical Protein Kinase C (Cpkc) Subtymentioning

confidence: 99%

Targeting protein kinase C subtypes in pancreatic cancer

Störz

2015

Expert Review of Anticancer Therapy

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“…Earlier studies demonstrated that PDAC cell lines express multiple PKCs, including α, β, ε and η [12–14]. Furthermore, a number of reports indicate an important role of PKCs in promoting proliferation and in preventing apoptosis of pancreatic cancer cells [12, 14–16] though a different view was also expressed [17]. A recent study demonstrates that atypical PKCι is required for the transformed growth of PDAC cells in vitro and their tumorigenesis in vivo [18].…”

Section: Protein Kinase C (Pkc) Isoforms and Pancreatic Ductal Adementioning

confidence: 99%

Role of protein kinase D signaling in pancreatic cancer

Guha

Tanasanvimon

Sinnett‐Smith

2010

Biochemical Pharmacology

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with dismal survival rates. Its intransigence to conventional therapy renders PDAC an aggressive disease with early metastatic potential. Thus, novel targets for PDAC therapy are urgently needed. Multiple signal transduction pathways are implicated in progression of PDAC. These pathways stimulate production of intracellular messengers in their target cells to modify their behavior, including the lipid-derived diacylglycerol (DAG). One of the prominent intracellular targets of DAG is the protein kinase C (PKC) family. However, the mechanisms by which PKC-mediated signals are decoded by the cell remain incompletely understood. Protein kinase D1 (PKD or PKD1, initially called atypical PKCµ), is the founding member of a novel protein kinase family that includes two additional protein kinases that share extensive overall homology with PKD, termed PKD2, and PKD3. The PKD family occupies a unique position in the signal transduction pathways initiated by DAG and PKC. PKD lies downstream of PKCs in a novel signal transduction pathway implicated in the regulation of multiple fundamental biological processes. We and others have shown that PKD-mediated signaling pathways promote mitogenesis and angiogenesis in PDAC. Our recent observations demonstrate that PKD also potentiates chemoresistance and invasive potential of PDAC cells. This review will briefly highlight diverse biological roles of PKD family in multiple neoplasias including PDAC. Further, this review will underscore our latest advancement with the development of a potent PKD family inhibitor and its effect both in vitro and in vivo in PDAC.

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“…Earlier studies demonstrated that PDAC cell lines express multiple PKCs, including α, β, ε, and η (Denham et al, 1998; Guha et al, 2002; Ishino et al, 2002). Furthermore, a number of reports indicate an important role of PKCs in promoting proliferation and in preventing apoptosis of PDAC cells (Denham et al, 1998; Trauzold et al, 2001; Ishino et al, 2002; Way et al, 2002; Guha et al, 2003) though a different view was also expressed (Detjen et al, 2000). A recent study demonstrated that atypical PKCι is required for the transformed growth of PDAC cells in vitro and their tumorigenesis in vivo (Scotti et al, 2010).…”

mentioning

confidence: 99%

Protein kinase D1 promotes anchorage‐independent growth, invasion, and angiogenesis by human pancreatic cancer cells

Ochi

Tanasanvimon

Matsuo

et al. 2011

Journal Cellular Physiology

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases. Novel molecularly targeted therapies are urgently needed. Here, we extended our studies on the role of protein kinase D1 (PKD1) in PDAC cell lines. Given that Panc-1 express moderate levels of PKD1, we used retroviral-mediated gene transfer to create a Panc-1 derivative that stably over-expresses PKD1 (Panc-1-PKD1). Reciprocally, we used shRNA targeting PKD1 in Panc-28 to produce a PKD1 under-expressing Panc-28 derivative (Panc-28-shPKD1). Our results demonstrate that Panc-1-PKD1 cells exhibit significantly increased anchorage-independent growth in soft agar and increased in vitro invasion compared with Panc-1-mock. Reciprocally, Panc-28-shPKD1 cells show a significant decrease in anchorage-independent growth and invasiveness, as compared with Panc-28-mock cells. The selective PKD family inhibitor CRT0066101 markedly decreased colony-forming ability and invasiveness by either Panc-1-PKD1 or Panc-28-mock cells. Secretion of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and CXC chemokines (CXCL8) was significantly elevated by PKD1 over-expression in Panc-1 cells and reduced either by depletion of PKD1 via shRNA in Panc-28 cells or by addition of CRT0066101 to either Panc-1-PKD1 or Panc-28-mock cells. Furthermore, human umbilical vein endothelial cell (HUVEC) tube formation was significantly enhanced by co-culture with Panc-1-PKD1 compared with Panc-1-mock in an angiogenesis assay in vitro. Conversely, PKD1 depletion in Panc-28 cells decreased their ability to induce endotube formation by HUVECs. PDAC-induced angiogenesis in vitro and in vivo was markedly inhibited by CRT0066101. Our results lend further support to the hypothesis that PKD family members provide a novel target for PDAC therapy.

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A protein kinase C inhibitor induces phenotypic reversion of ras -transformed pancreatic cancer cells and cooperatively blocks tumor cell proliferation with an anti- ras peptide

Cited by 8 publications

References 9 publications

Targeting protein kinase C subtypes in pancreatic cancer

Targeting protein kinase C subtypes in pancreatic cancer

Role of protein kinase D signaling in pancreatic cancer

Protein kinase D1 promotes anchorage‐independent growth, invasion, and angiogenesis by human pancreatic cancer cells

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