Targeting atypical protein kinase C iota reduces viability in glioblastoma stem‐like cells <i>via</i> a notch signaling mechanism

Phillips, Emma; Lang, Verena; Bohlen, Jonathan; Bethke, Frederic; Puccio, Laura; Tichy, Diana; Herold‐Mende, Christel; Hielscher, Thomas; Lichter, Peter; Goidts, Violaine

doi:10.1002/ijc.30234

Cited by 31 publications

(25 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results suggest that PKCλ, but not PKCζ, is involved in c-Met-dependent cell proliferation and tumor formation, as well as other actions of ALDH1-positive breast CSCs. Remarkably, PKCλ controls the Notch signal pathway, a key driver of stemness in KRAS-mediated lung adenocarcinoma (LADC) (43) and in glioblastoma (44). In addition, PKCλ controls signaling by SOX2-hedgehog acyl transferase (HHAT), a master transcriptional regulator of stemness, in lung squamous cell carcinoma (42).…”

Section: Discussionmentioning

confidence: 99%

High Expression of c-Met, PKCλ and ALDH1A3 Predicts a Poor Prognosis in Late-stage Breast Cancer

et al. 2019

View full text Add to dashboard Cite

Background/Aim: Co-expression of c-Met and ALDH1A3 indicates a poor prognosis in stage III-IV breast cancers and contributes to cell proliferation and tumor formation by ALDH1-positive breast CSCs. PKCλ is overexpressed and contributes to a poor prognosis in several cancers. Materials and Methods: A breast cancer genomics data set (METABRIC, n=2509) was downloaded and analyzed, as was the effect c-Met and PKCλ inhibitors on ALDH1 high cell viability and tumor-sphere formation. Results: c-Met expression correlates with expression of PKCλ in breast cancer. Stage III-IV breast cancer patients with c-Met high PKCλ high ALDH1A3 high have a poorer prognosis than patients with c-Met low PKCλ low ALDH1A3 low. Foretinib and auranofin suppressed cell viability and tumor-sphere formation by ALDH1 high cells. These results suggest that c-Met and PKCλ are cooperatively involved in cancer progression and contribute to poor prognoses in breast cancer. Conclusion: c-Met and PKCλ are potentially useful prognostic markers and therapeutic targets in late-stage breast cancer. Breast cancer is the second most frequently diagnosed cancer worldwide, and the most commonly occurring cancer among women, with 2.09 million new cases (24.2% of all cancers in women) and 0.6 million cancer-related deaths annually (1). Breast cancers are classified based on their gene expression pattern (PAM 50) into at least six subtypes, including normallike, luminal A, luminal B, HER2-enriched, claudin-low and basal-like (2-5). Among these, basal-like breast cancers have stem-like properties and a poor prognosis (4). Nonetheless, the prognosis for breast cancer patients is good overall, though it is significantly poorer for patients with late-stage tumors (stage III or IV) (6). This is in large part because late-stage breast cancers are often resistant to standard medical treatments, such as conventional surgery, chemotherapy, and radiotherapy, which is reflected in their recurrence and metastasis (6). Consequently, the new pharmacological approach to managing late-stage breast cancers is greatly needed. Tumors are composed of populations of cancer cells and distinct cancer stem cells (CSCs), which are largely undifferentiated tumorigenic cells that exhibit such stem-like properties as self-renewal and multipotency (7, 8). Most CSCs are resistant to conventional chemo-and radiotherapies, and the development of targeted therapies against CSCs is very much needed to improve clinical outcomes. CSCs within breast tumors can be identified based on their expression of CD44, CD24 and aldehyde dehydrogenase 1 (ALDH1) (9, 10). ALDH1 is an enzyme that converts aldehydes to carboxylic acids and is abundant in normal stem/progenitor cells, and various CSCs, including those in breast cancers (9, 11). Among the ALDH1 gene family, ALDH1A1 and ALDH1A3 are known to be CSC markers in several cancers (12-17). In particular, ALDH1A3 reportedly contributes significantly to the ALDH1 activity detected in breast cancer cells, and its expression correlates significantly with cancer...

show abstract

Section: Discussionmentioning

confidence: 99%

High Expression of c-Met, PKCλ and ALDH1A3 Predicts a Poor Prognosis in Late-stage Breast Cancer

et al. 2019

View full text Add to dashboard Cite

show abstract

“…In addition, Notch signaling dysregulation has also been recognized in glioblastoma CSCs [82]. It was found that Protein Kinase C Iota (PKCi) was highly expressed in glioblastoma patient-derived CSCs, and silencing PKCi resulted in apoptosis and reduction of proliferation of the glioblastoma CSCs in vitro and tumor growth in vivo in a xenograft mouse model [83]. Gene expression profiling of PKCi-silenced glioblastoma CSCs revealed a novel role of the Notch signaling pathway in PKCi mediated glioblastoma CSC's survival [83].…”

Section: Signaling Pathways In Cscsmentioning

confidence: 99%

“…It was found that Protein Kinase C Iota (PKCi) was highly expressed in glioblastoma patient-derived CSCs, and silencing PKCi resulted in apoptosis and reduction of proliferation of the glioblastoma CSCs in vitro and tumor growth in vivo in a xenograft mouse model [83]. Gene expression profiling of PKCi-silenced glioblastoma CSCs revealed a novel role of the Notch signaling pathway in PKCi mediated glioblastoma CSC's survival [83]. In addition to its important roles in CSCs, Notch signaling is also involved in EMT to promote cancer cell acquisition of a stem-like phenotype and drug resistance.…”

Section: Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting Signaling Pathways in Cancer Stem Cells for Cancer Treatment

Koury

Zhong

Hao

2017

Stem Cells International

117

View full text Add to dashboard Cite

The Wnt, Hedgehog, and Notch pathways are inherent signaling pathways in normal embryogenesis, development, and hemostasis. However, dysfunctions of these pathways are evident in multiple tumor types and malignancies. Specifically, aberrant activation of these pathways is implicated in modulation of cancer stem cells (CSCs), a small subset of cancer cells capable of self-renewal and differentiation into heterogeneous tumor cells. The CSCs are accountable for tumor initiation, growth, and recurrence. In this review, we focus on roles of Wnt, Hedgehog, and Notch pathways in CSCs' stemness and functions and summarize therapeutic studies targeting these pathways to eliminate CSCs and improve overall cancer treatment outcomes.

show abstract

“…Following genes were targeted: TP53 (gRNA: GT GAG GCT CCC CTT TCT TG), LIG4 (gRNA: GAC GGA AAA GAT ACC TCG G). Virus production and transduction as described previously 27 ; in brief, pLentiV2, pDMDG.2, and pSPAX were co-transfected in HEK293T cells, and viruscontaining supernatant was concentrated by ultra-centrifugation. Transduction was done by adding concentrated virus particles to both NSC cell lines for 24hours, after which cells were maintained under selection either with puromycin or blasticidin at 2ug/mL for at least 2 weeks.…”

Section: Crispr-cas Targeted Gene Disruptionmentioning

confidence: 99%

Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors

Ratnaparkhe

Wong

Wei

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent chromothripsis or chromoanasynthesis (n= 16/26) in brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or nonhomologous-end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n=68) and glioblastomas (n=32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumors with complex genomic rearrangements.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/314518 doi: bioRxiv preprint first posted online May. 4, 2018; 3 Chromothripsis and chromoanasynthesis are two forms of genomic instability that lead to complex genomic rearrangements affecting one or very few chromosomes [1][2][3] . These two types of catastrophic events play a role in numerous tumor entities as well as in some congenital diseases 3,4 . The first form, chromothripsis, is characterized by the simultaneous occurrence of tens to hundreds of clustered DNA double-strand breaks 1,5 . The DNA fragments resulting from this shattering event are re-ligated by error-prone repair processes, with some of the fragments being lost. The outcome is a highly rearranged derivative chromosome, with oscillations between two or three copy-number states 6 . Conversely, the local rearrangements arising from chromoanasynthesis exhibit altered copy number due to serial microhomologymediated template switching during DNA replication 2 . Resynthesis of fragments from one chromatid and frequent insertions of short sequences between the rearrangement junctions are associated with copy number gains and retention of heterozygosity 2 .The availability of murine tumor models recapitulating these phenomena would substantially facilitate the investigation of the mechanistic aspects underlying chromothripsis and chromoanasynthesis. We showed previously the role of constitutive and somatic DNA repair defects in catastrophic genomic events in the context of TP53 and ATM mutations 5,7 . Further factors essential to the biochemical and signaling context of occurrence of these catastrophic events remain to be identified, and the role of repair processes in chromothripsis and chromoanasynthesis needs to be better defined.Homologous recombination repair (HR) and canonical non-homologous endjoining (cNHEJ) represent the two major repair processes for DNA double-strand breaks in mammalian cells. Conditional inactivation of key repair factors of either of these t...

show abstract

Targeting atypical protein kinase C iota reduces viability in glioblastoma stem‐like cells via a notch signaling mechanism

Cited by 31 publications

References 36 publications

High Expression of c-Met, PKCλ and ALDH1A3 Predicts a Poor Prognosis in Late-stage Breast Cancer

High Expression of c-Met, PKCλ and ALDH1A3 Predicts a Poor Prognosis in Late-stage Breast Cancer

Targeting Signaling Pathways in Cancer Stem Cells for Cancer Treatment

Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors

Contact Info

Product

Resources

About