Protein kinase C δ enhances proliferation and survival of murine mammary cells

Grossoni, Valeria C.; Falbo, Karina B.; Kazanietz, Marcelo G.; Joffé, Elisa D. Bal de Kier; Urtreger, Alejandro J.

doi:10.1002/mc.20287

Cited by 68 publications

(81 citation statements)

References 50 publications

(59 reference statements)

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“…PI 3-kinase-dependent activation of Akt is mediated by PKC-␦, which is required for cell survival in various cancer and immune cells (1,2,28). However, Zhong et al suggested that PKC-␦ downregulation suppresses apoptotic signals through a novel PI 3-kinase-independent survival pathway (29).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C-δ Mediates Neuronal Apoptosis in the Retinas of Diabetic Rats via the Akt Signaling Pathway

Kim

Park

et al. 2008

Diabetes

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OBJECTIVE-Protein kinase C (PKC)-␦, an upstream regulator of the Akt survival pathway, contributes to cellular dysfunction in the pathogenesis of diabetes. Herein, we examined the role of PKC-␦ in neuronal apoptosis through Akt in the retinas of diabetic rats.RESEARCH DESIGN AND METHODS-We used retinas from 24-and 35-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) diabetic and Long-Evans Tokushima Otsuka (LETO) nondiabetic rats. To assess whether PKC-␦ affects Akt signaling and cell death in OLETF rat retinas, we examined 1) PKC-␦ activity and apoptosis; 2) protein levels of phosphatidylinositol 3-kinase (PI 3-kinase) p85, heat shock protein 90 (HSP90), and protein phosphatase 2A (PP2A); 3) Akt phosphorylation; and 4) Akt binding to HSP90 or PP2A in LETO and OLETF retinas in the presence or absence of rottlerin, a highly specific PKC-␦ inhibitor, or small interfering RNAs (siRNAs) for PKC-␦ and HSP90.RESULTS-In OLETF retinas from 35-week-old rats, ganglion cell death, PKC-␦ and PP2A activity, and Akt-PP2A binding were significantly increased and Akt phosphorylation and Akt-HSP90 binding were decreased compared with retinas from 24-week-old OLETF and LETO rats. Rottlerin and PKC-␦ siRNA abrogated these effects in OLETF retinas from 35-week-old rats. HSP90 siRNA significantly increased ganglion cell death and Akt-PP2A complexes and markedly decreased HSP90-Akt binding and Akt phosphorylation in LETO retinas from 35-week-old rats compared with those from nontreated LETO rats.CONCLUSIONS-PKC-␦ activation contributes to neuro-retinal apoptosis in diabetic rats by inhibiting Akt-mediated signaling pathways. Diabetes 57:2181-2190, 2008 P rotein kinase C (PKC)-␦, a ubiquitously expressed isoform of the novel PKC subfamily, mediates an anti-apoptotic signaling cascade through the phosphatidylinositol 3-kinase (PI 3-kinase)-mediated survival pathway (1,2) and also promotes apoptosis by interfering with Akt signaling (3-5).Akt is a downstream target of PI 3-kinase that plays an integral role in cell survival. Dysregulation of Akt is frequently observed in diseases such as cancers and diabetes (6 -8). PI 3-kinase activates Akt through the phosphorylation of two key regulatory residues, Thr308 and Ser473, on Akt. Phosphorylation of both residues is necessary for full activation of Akt and subsequent regulation of many PI 3-kinase-mediated biological responses (9,10).Protein phosphatase 2A (PP2A), a major cellular serine/ threonine phosphatase, regulates the phosphorylation state of cellular proteins in various pathological conditions (11-13). Recently, it has been reported that PP2A is involved in the regulation of cell proliferation and survival through its ability to dephosphorylate Akt (11-15). Furthermore, heat shock protein 90 (HSP90) counteracts the effect of PP2A in cells through direct binding to Akt, protecting Akt from PP2A-mediated dephosphorylation and thus functioning as a positive regulator of Akt signaling (13,15,16). Of note, numerous reports have suggested that Akt-or HSP-mediated cytoprotection is r...

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Section: Discussionmentioning

confidence: 99%

Protein Kinase C-δ Mediates Neuronal Apoptosis in the Retinas of Diabetic Rats via the Akt Signaling Pathway

Kim

Park

et al. 2008

Diabetes

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“…Studies of PKCδ in estrogen-responsive tissues have been contradictory. PKCδ increased proliferative and survival capacities in an immortal- ized mammary cell line (23). Estrogen has been reported to stimulate the expression of PKCδ in the corpus luteum (24), but to downregulate the expression of PKCδ in MCF-7 cells (20).…”

Section: Introductionmentioning

confidence: 97%

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

Xie

2012

Oncol Rep

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Abstract. This study was designed to investigate the role of protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in tamoxifen (TAM)-induced apoptosis and drug resistance in human breast cancer cells. Drug-sensitive, or estrogen receptor (ER)-positive human breast carcinoma cells (MCF-7) and the multi-drug-resistant variant (ER-negative) MCF-7/ADR cells were treated with doses of TAM for various periods of time. Cell viability and apoptosis were assessed using cell counting, DNA fragmentation and flow cytometric analysis. We found that TAM administration caused a significant increase in apoptosis of MCF-7 cells but not MCF-7/ADR cells. Western blot analysis revealed enhanced expression of PKCδ but decreased expression of PKCα in ER-positive MCF-7 cells; while ER-negative MCF-7/ADR cells had decreased levels of PKCδ and increased levels of PKCα. Interestingly, we observed that in MCF-7 cells, TAM stimulated apoptosis by promoting rapid activation of PKCδ, antagonizing downstream signaling of ERK phosphorylation; while in MCF-7/ADR cells, TAM upregulated PKCα, which promoted ERK phosphorylation. These results suggest that PKCδ enhances apoptosis in TAM-treated MCF-7 cells by antagonizing ERK phosphorylation; while the PKCα pathway plays an important role in TAM-induced drug resistance by activating ERK signaling in MCF-7/ADR cells. The combination of TAM with PKCα and ERK inhibitors could promote TAM-induced apoptosis in breast cancer cells. IntroductionBreast cancer is a common malignancy in females and the second cause of death from cancer in women today (1). Treatment for breast cancer includes surgery, chemotherapy, radiotherapy and endocrine therapy. Tamoxifen (TAM), an antagonist of the estrogen receptor (ER), is a selective ER modulator (SERM). TAM is a front-line endocrine therapeutic drug for ER-positive breast cancers. Results from TAM therapy showed a 40-50% reduction in the risk of cancer recurrence and cancer mortality (2). Recently, TAM has been demonstrated to be effective for some ER-negative breast cancers, as well as other types of cancers, including gliomas. These data suggest that TAM may also be implicated in ER-independent antitumor mechanisms (3,4). Of note, some advanced breast cancers that initially respond well to TAM eventually become refractory to treatment (5-9). Thus, the traditional mechanism of TAM action through the ER is challenged, and other noncanonical pathways need to be explored.Protein kinase C (PKC), a family of serine/threonine kinases, is involved in many important cellular functions, including cell proliferation, migration, differentiation, and apoptosis (10-12). Twelve PKC isoforms have been discovered in various cell types, including conventional PKCs (cPKCα, βI/βII and γ), novel PKCs (nPKCδ, ε, η), and atypical PKCs (aPKCζ) (13,14). The expression of PKCα, δ, ε, η, γ, μ, and ζ has been detected in MCF-7 cells (15,16); PKCα is a marker for anti-estrogen resistance and is involved in the growth of TAM-resistant human breast cancer cell...

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“…Moreover, there is a substantial body of evidence linking PKC to the initiation and progression of certain types of cancers, including gliomas, and breast, pancreatic and colon cancers (Alonso-Escolano et al, 2006;Bredel and Pollack, 1997;El-Rayes et al, 2008;Gokmen-Polar et al, 2001;Grossoni et al, 2007). Total PKC expression and activity levels are significantly higher in normal brain tissue than in non-brain tissues, suggesting that this serine/threonine kinase has a fundamental role in normal brain physiology (Nelsona and Alkona, 2009;Steinhart et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Importance of PKCδ signaling in fractionated-radiation-induced expansion of glioma-initiating cells and resistance to cancer treatment

Kim

Yoon

et al. 2011

Journal of Cell Science

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SummaryBrain tumors frequently recur or progress as focal masses after treatment with ionizing radiation. However, the mechanisms underlying the repopulation of tumor cells after radiation have remained unclear. In this study, we show that cellular signaling from Abelson murine leukemia viral oncogene homolog (Abl) to protein kinase Cd (PKCd) is crucial for fractionated-radiation-induced expansion of gliomainitiating cell populations and acquisition of resistance to anticancer treatments. Treatment of human glioma cells with fractionated radiation increased Abl and PKCd activity, expanded the CD133-positive (CD133 + ) cell population that possesses tumor-initiating potential and induced expression of glioma stem cell markers and self-renewal-related proteins. Moreover, cells treated with fractionated radiation were resistant to anticancer treatments. Small interfering RNA (siRNA)-mediated knockdown of PKCd expression blocked fractionated-radiation-induced CD133 + cell expansion and suppressed expression of glioma stem cell markers and self-renewal-related proteins. It also suppressed resistance of glioma cells to anticancer treatments. Similarly, knockdown of Abl led to a decrease in CD133 + cell populations and restored chemotherapeutic sensitivity. It also attenuated fractionated-radiation-induced PKCd activation, suggesting that Abl acts upstream of PKCd. Collectively, these data indicate that fractionated radiation induces an increase in the glioma-initiating cell population, decreases cellular sensitivity to cancer treatment and implicates activation of Abl-PKCd signaling in both events. These findings provide insights that might prove pivotal in the context of ionising-radiation-based therapeutic interventions for brain tumors.

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Protein kinase C δ enhances proliferation and survival of murine mammary cells

Cited by 68 publications

References 50 publications

Protein Kinase C-δ Mediates Neuronal Apoptosis in the Retinas of Diabetic Rats via the Akt Signaling Pathway

Protein Kinase C-δ Mediates Neuronal Apoptosis in the Retinas of Diabetic Rats via the Akt Signaling Pathway

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

Importance of PKCδ signaling in fractionated-radiation-induced expansion of glioma-initiating cells and resistance to cancer treatment

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