Knockdown of PKR expression by RNAi reduces pulmonary metastatic potential of B16-F10 melanoma cells in mice: Possible role of NF-κB

André, Nayara Delgado; Lucca, Fernando Luiz De

doi:10.1016/j.canlet.2007.08.021

Cited by 17 publications

(24 citation statements)

References 31 publications

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“…For example, transfection of NIH 3T3 cells with a functionally defective mutant PKR led to malignant transformation [24]. However, knockdown of PKR reduces pulmonary metastatic potential of murine melanoma dramatically, which is mediated by the transcription factor NF-κB [25]. In addition, as the expression of PKR and prognosis for certain tumors is concerned, different clinical observations contradicted each other [26].…”

Section: Discussionmentioning

confidence: 89%

An armed oncolytic adenovirus ZD55-IL-24 combined with ADM or DDP demonstrated enhanced antitumor effect in lung cancer

Zhong

Wang

et al. 2010

Acta Oncologica

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Section: Discussionmentioning

confidence: 89%

An armed oncolytic adenovirus ZD55-IL-24 combined with ADM or DDP demonstrated enhanced antitumor effect in lung cancer

Zhong

Wang

et al. 2010

Acta Oncologica

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“…Thus, previously it was suggested that PKR acts as a tumor suppressor by inhibiting cell growth and inducing apoptosis (62, 63). In contrast, more recent studies suggest PKR has an anti-apoptotic role in regulating tumor development and tumor cell apoptosis (6-9). Elevated PKR protein level and activity were observed in certain tumor cells, i.e., human breast cancer cells (6), melanoma cells (7, 9), and hepatitis C virus (HCV)-related hepatocellular carcinoma (8).…”

Section: Discussionmentioning

confidence: 98%

“…In contrast, more recent studies suggest PKR has an anti-apoptotic role in regulating tumor development and tumor cell apoptosis (6-9). Elevated PKR protein level and activity were observed in certain tumor cells, i.e., human breast cancer cells (6), melanoma cells (7, 9), and hepatitis C virus (HCV)-related hepatocellular carcinoma (8). The over-expression and elevated activity of PKR have been attributed to the development of tumor, and the proliferation of tumor cells (6-9), but the mechanism is still unclear.…”

Section: Discussionmentioning

confidence: 98%

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Repression of PKR mediates palmitate-induced apoptosis in HepG2 cells through regulation of Bcl-2

Yang

Chan

2009

Cell Res

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In the present study we found that double-stranded RNA-dependent protein kinase (PKR) regulates the protein expression level and the phosphorylation of Bcl-2 and exploits an anti-apoptotic role in human hepatocellular carcinoma cells (HepG2). Saturated free fatty acids (FFAs), e.g. palmitate, have been shown to induce cellular apoptosis in various types of cells by different mechanisms. We found palmitate down-regulates the activity of PKR, and thereby decreases the protein level of Bcl-2, mediated, in part, by the NF-κB transcription factor. In addition to the protein level of Bcl-2, the phosphorylation of Bcl-2 at different amino acid residues, such as Ser70 and Ser87, is also important in regulating cellular apoptosis. The decrease in the phosphorylation of Bcl-2 at Ser70 upon exposure to palmitate is mediated by PKR and possibly JNK, while the phosphorylation of Bcl-2 at Ser87 is not affected by palmitate or PKR. In summary, PKR mediates the regulation of the protein level and the phosphorylation status of Bcl-2, providing a novel mechanism of palmitate-induced apoptosis in HepG2 cells.

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“…As proof of principal for this concept, injection of melanoma tumor cells transfected with a PKR-specific short hairpin RNA (shRNA) expressing plasmid resulted in inhibition of pulmonary metastatic nodules in mice 39. In primary human thyroid carcinomas, Terada et al, reported significant correlations between high PKR expression, vascular invasion, and the presence of satellite tumor nodules 40.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of RNA-dependent protein kinase (PKR) leads to cancer cell death and increases chemosensitivity

Pataer¹,

Swisher²,

Roth³

et al. 2009

Cancer Biology & Therapy

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RNA-dependent protein kinase is an interferon-induced, double-stranded (ds), RNA-activated serine/threonine protein kinase involved in the eukaryotic response to viral infection. While PKR also functions in cellular differentiation, growth control and apoptosis, its role in human cancer remains poorly understood. To explore a role for PKR in human cancer, we evaluated PKR expression and function in a series of cancer cell lines from different tumor types. We observed that PKR protein expression is high in various cancer cells and low in normal cells. Knockdown of PKR protein expression by PKR siRNA induced cell death, indicating a PKR-dependent survival pathway under normal growth conditions. Inhibition of PKR signaling using a dominant negative adenoviral PKR mutant (Ad-Δ6PKR) also induced cancer cell apoptosis via a mechanism that blocks activation of AKT-mediated survival while simultaneously inducing ER stress. ER stress-mediated apoptosis was evidenced by unregulated expression of phosphorylated JNK (p-JNK), phosphorylated cJun (p-cJun), and caspase-4 and was significantly reduced in cancer cells treated with JNK and caspase-4 inhibitors. We further demonstrated that inhibition of PKR signaling via either siRNA or Ad-Δ6PKR sensitizes cancer cells to etoposide or cisplatin-mediated cell death. Our results suggest a rationale to develop therapeutic strategies that target PKR signaling in human cancer cells.

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Knockdown of PKR expression by RNAi reduces pulmonary metastatic potential of B16-F10 melanoma cells in mice: Possible role of NF-κB

Cited by 17 publications

References 31 publications

An armed oncolytic adenovirus ZD55-IL-24 combined with ADM or DDP demonstrated enhanced antitumor effect in lung cancer

An armed oncolytic adenovirus ZD55-IL-24 combined with ADM or DDP demonstrated enhanced antitumor effect in lung cancer

Repression of PKR mediates palmitate-induced apoptosis in HepG2 cells through regulation of Bcl-2

Inhibition of RNA-dependent protein kinase (PKR) leads to cancer cell death and increases chemosensitivity

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