Atypical Protein Kinase C ζ Exhibits a Proapoptotic Function in Ovarian Cancer

Nazarenko, Irina; Jenny, M; Keil, Jana; Gieseler, Cornelia; Weißhaupt, Karen; Sehouli, Jalid; Legewie, Stefan; Herbst, Lena; Weichert, Wilko; Darb‐Esfahani, Silvia; Dietel, Manfred; Schäfer, Reinhold; Ueberall, Florian; Sers, Christine

doi:10.1158/1541-7786.mcr-09-0358

Cited by 26 publications

(26 citation statements)

References 71 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results are in agreement with previous reports showing that caspase activation and apoptosis promoted by activated G␣q is not blocked by inhibitors of IP 3 -or PKC-dependent signaling (38). Also, the role of PKC as a pro-apoptotic protein appears to have a crucial effect on the repression of tumorigenesis in ovarian (39) and prostate cancer (40). Interestingly, pharmacological blockade of ERK5 partly inhibited cell death promotion downstream of the Gq/PKC axis.…”

Section: Discussionsupporting

confidence: 93%

Protein Kinase C ζ Interacts with a Novel Binding Region of Gαq to Act as a Functional Effector

Sánchez-Fernández

Cabezudo

Hernandez-Caballero

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Heterotrimeric G proteins play an essential role in the initiation of G protein-coupled receptor (GPCR) signaling through specific interactions with a variety of cellular effectors. We have recently reported that GPCR activation promotes a direct interaction between G␣q and protein kinase C (PKC), leading to the stimulation of the ERK5 pathway independent of the canonical effector PLC␤. We report herein that the activation-dependent G␣q/PKC complex involves the basic PB1-type II domain of PKC and a novel interaction module in G␣q different from the classical effector-binding site. Point mutations in this G␣q region completely abrogate ERK5 phosphorylation, indicating that G␣q/PKC association is required for the activation of the pathway. Indeed, PKC was demonstrated to directly bind ERK5 thus acting as a scaffold between G␣q and ERK5 upon GPCR activation. The inhibition of these protein complexes by G proteincoupled receptor kinase 2, a known G␣q modulator, led to a complete abrogation of ERK5 stimulation. Finally, we reveal that G␣q/ PKC complexes link G␣q to apoptotic cell death pathways. Our data suggest that the interaction between this novel region in G␣q and the effector PKC is a key event in G␣q signaling.

show abstract

Section: Discussionsupporting

confidence: 93%

Protein Kinase C ζ Interacts with a Novel Binding Region of Gαq to Act as a Functional Effector

Sánchez-Fernández

Cabezudo

Hernandez-Caballero

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…On the other hand, PKC in ovarian cancer cells can act as a negative regulator of cell survival via regulation of the proapoptotic functions of protein phosphatase 2A (a survival phosphatase) and HRSL3 (a class II tumor suppressor family; also known as H-REV107-1) [394].…”

Section: Ovarianmentioning

confidence: 99%

Protein Kinase C (PKC) Isozymes and Cancer

Kang

2014

New Journal of Science

View full text Add to dashboard Cite

Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine kinases, which can be further classified into three PKC isozymes subfamilies: conventional or classic, novel or nonclassic, and atypical. PKC isozymes are known to be involved in cell proliferation, survival, invasion, migration, apoptosis, angiogenesis, and drug resistance. Because of their key roles in cell signaling, PKC isozymes also have the potential to be promising therapeutic targets for several diseases, such as cardiovascular diseases, immune and inflammatory diseases, neurological diseases, metabolic disorders, and multiple types of cancer. This review primarily focuses on the activation, mechanism, and function of PKC isozymes during cancer development and progression.

show abstract

“…Contentious opinions have been expressed in the past about the pro-or anti-apoptotic roles played by PKCζ (39)(40)(41). Our results from proteomics analysis clearly demonstrated that PKCζ changed nearly 86% of its interacting proteins at the NMs of C4-I cells.…”

Section: Discussionmentioning

confidence: 65%

Bcl10 crucially nucleates the pro-apoptotic complexes comprising PDK1, PKCζ and caspase-3 at the nuclear envelope of etoposide-treated human cervical carcinoma C4-I cells

Chiarini

Liu

Armato

et al. 2015

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Abstract. Protein kinase (PK)Cζ signaling at various subcellular levels affects cell survival, differentiation, growth and/or apoptosis. However, the mechanisms modulating PKCζ activity at the nuclear membrane (NM) are not yet fully understood. Previously, we demonstrated that PKCζ interacts with the B-cell lymphoma 10 (Bcl10) protein at the NM of human cervical carcinoma (HCC) C4-I cells. In the present study, we aimed to further clarify the interactions between PKCζ, Bcl10 and other proteins co-immunoprecipitated from NMs isolated from untreated and etoposide (also known as VP-16; 2.0 µg/ml)-treated C4-I cells using biochemical and proteomics analyses. Aside from the Bcl10 protein, 3-phosphoinositide-dependent protein kinase-1 (PDK1) also co-immunoprecipitated with PKCζ from NMs of C4-I cells, indicating the assembly of a heterotrimeric complex, which increased with time in VP-16-exposed cells, as did the activity of PDK1-phosphorylated-PKCζ. In turn, PKCζ-phosphorylated-Bcl10 straddled an enlarged complex which comprised caspase-3. Subsequently, activity-enhanced caspase-3 cleaved and inactivated PKCζ. Finally, the suppression of Bcl10 using specific siRNA or lentiviral transduction prevented the increase in the PDK1•PKCζ association, the increase in the activity of PKCζ and caspase-3, as well as the caspase-3-mediated PKCζ proteolysis and inactivation from occurring at the NMs of the VP-16-exposed C4-I cells. Our observations provide evidence that Bcl10 acts as a pivotal pro-apoptotic protein which crucially nucleates complexes comprising PDK1, PKCζ and active caspase-3 at the NMs of VP-16-exposed C4-I cells. Hence, our data suggest that Bcl10 and PKCζ are potential therapeutic targets in the treatment of HCC. IntroductionThe disease with the second highest rate of mortality, for women, is human cervical carcinoma (HCC), which is prevalent in developing countries (1,2). The majority of HCCs derive from epithelial cells that have been persistently infected with high-risk oncogenic human papillomaviruses (HPVs), which express the E6 and E7 mRNAs, and proteins binding/neutralizing anti-oncogenic p53 and pRb. Furthermore, other co-factors, which have been less thoroughly studied, also promote HCC development (3,4). Notably, a small percentage (10%) of HCCs develops independently of a persistent high-risk oncogenic HPV infection (5). The complex molecular mechanisms responsible for the development of HCCs thus remain partially unclear, and this hinders the identification of predictive markers for the early detection of malignancy development and the discovery of novel, effective therapies.Proteomics and bioinformatics analysis have allowed researchers to identify differential protein expression patterns and the molecular mechanisms responsible for the development of HCC (6). A previous study identified a consensus of 66 proteins termed the 'central core of HCC protein expression̓ which was deduced from the proteomes of 6 HCC cell lines (not comprising the C4-I cell line); this differed from the proteomic profile...

show abstract

Atypical Protein Kinase C ζ Exhibits a Proapoptotic Function in Ovarian Cancer

Cited by 26 publications

References 71 publications

Protein Kinase C ζ Interacts with a Novel Binding Region of Gαq to Act as a Functional Effector

Protein Kinase C ζ Interacts with a Novel Binding Region of Gαq to Act as a Functional Effector

Protein Kinase C (PKC) Isozymes and Cancer

Bcl10 crucially nucleates the pro-apoptotic complexes comprising PDK1, PKCζ and caspase-3 at the nuclear envelope of etoposide-treated human cervical carcinoma C4-I cells

Contact Info

Product

Resources

About