PRKCQ promotes oncogenic growth and anoikis resistance of a subset of triple-negative breast cancer cells

Byerly, Jessica H.; Halstead-Nussloch, Gwyneth; Ito, Koichi; Katsyv, Igor; Irie, Hanna Y.

doi:10.1186/s13058-016-0749-6

Cited by 35 publications

(35 citation statements)

References 36 publications

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“…PARD6B) and tyrosine kinases (e.g. SRC, PRKCQ, and CSNK2A1) with major roles in the disruption of adherent junctions, anoikis resistance, and cell migration 45,49,50 (Table 4).…”

Section: Analysis Of Common Cngs Significantly Correlated With Reducementioning

confidence: 99%

Analysis of Copy-Number Variations and Feline Mammary Carcinoma Survival

Granados-Soler

Bornemann-Kolatzki²,

Beck³

et al. 2020

Sci Rep

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Feline mammary carcinomas (FMCs) are highly malignant. As the disease-free survival (DFS) and overall survival (OS) are short, prognostication is crucial. Copy-number variations (CNVs) analysis by nextgeneration sequencing serves to identify critical cancer-related genomic regions. Thirty-three female cats with FMCs were followed during two years after surgery. Tumours represented tubulopapillary and solid carcinomas encompassing six molecular subtypes. Regardless of the histopathological diagnosis, molecular subtypes showed important differences in survival. Luminal A tumours exhibited the highest DFS (p = 0.002) and cancer-specific OS (p = 0.001), and the lowest amount of CNVs (p = 0.0001). In contrast, basal-like triple-negative FMCs had the worst outcome (DFS, p < 0.0001; and OS, p < 0.00001) and were the most aberrant (p = 0.05). In the multivariate analysis, copy-number losses (CNLs) in chromosome B1 (1-23 Mb) harbouring several tumour-repressors (e.g. CSMD1, MTUS1, MSR1, DBC2, and TUSC3) negatively influenced DFS. Whereas, copy-number gains (CNGs) in B4 (1-29 Mb) and F2 (64-82.3 Mb) comprising epithelial to mesenchymal transition genes and metastasis-promoting transcription factors (e.g. GATA3, VIM, ZEB1, and MYC) negatively influenced DFS and cancer-specific OS. These data evidence an association between specific CNVs in chromosomes B1, B4 and F2, and poor prognosis in FMCs.

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“…PARD6B) and tyrosine kinases (e.g. SRC, PRKCQ, and CSNK2A1) with major roles in the disruption of adherent junctions, anoikis resistance, and cell migration 45,49,50 (Table 4).…”

Section: Analysis Of Common Cngs Significantly Correlated With Reducementioning

confidence: 99%

Analysis of Copy-Number Variations and Feline Mammary Carcinoma Survival

Granados-Soler

Bornemann-Kolatzki²,

Beck³

et al. 2020

Sci Rep

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“…However, there is heterogeneity in sensitivity to chemotherapy among TNBC, and it is critical to identify targetable drivers of chemotherapy resistance. PRKCQ is a novel PKC family member, preferentially expressed in the TNBC subtype and drives growth factor-independent growth, anoikis resistance, migration, and EMT, all properties associated with tumorigenesis and metastatic spread of cancer cells [14,16,17,27]. EMT specifically is associated with chemotherapy resistance via multiple mechanisms in several tumor types (reviewed in [28]).…”

Section: Discussionmentioning

confidence: 99%

“…Cells were exposed to viral supernatant overnight before changing to complete media. PRKCQ mutants (A148E and K409R) were generated as previously described [14,19].…”

Section: Constructs Viral Production and Stable Cell Line Generationmentioning

confidence: 99%

“…Enhanced PRKCQ expression is sufficient to promote growth factor-independent growth, anoikis resistance, and migration of breast epithelial cells (MCF-10A) (Byerly et al [14]). PRKCQ overexpression is also sufficient to enhance the viability of these cells in the presence of chemotherapeutic agents commonly used in the treatment of patient triple-negative breast cancers, such as doxorubicin and paclitaxel (Fig.…”

Section: Kinase-active Prkcq Suppresses Chemotherapy-induced Apoptosismentioning

confidence: 99%

“…PRKCQ is expressed in a subset of GIST cancers and regulates their proliferation [13]. We previously reported that PRKCQ is sufficient to drive growth factor-independent proliferation, migration, and survival of breast epithelial cells by activating Erk/MAPK activity in a kinase activity-dependent manner [14]. PRKCQ protein is not only sufficient to drive these phenotypes but is required for growth in vitro and in vivo of triplenegative breast cancer cells in which it is expressed.…”

Section: Introductionmentioning

confidence: 99%

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PRKCQ inhibition enhances chemosensitivity of triple-negative breast cancer by regulating Bim

2020

Self Cite

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Background: Protein kinase C theta, (PRKCQ/PKCθ) is a serine/threonine kinase that is highly expressed in a subset of triple-negative breast cancers (TNBC) and promotes their growth, anoikis resistance, epithelial-mesenchymal transition (EMT), and invasion. Here, we show that PRKCQ regulates the sensitivity of TNBC cells to apoptosis triggered by standard-of-care chemotherapy by regulating levels of pro-apoptotic Bim. Methods: To determine the effects of PRKCQ expression on chemotherapy-induced apoptosis, shRNA and cDNA vectors were used to modulate the PRKCQ expression in MCF-10A breast epithelial cells or triple-negative breast cancer cells (MDA-MB231Luc, HCC1806). A novel PRKCQ small-molecule inhibitor, 17k, was used to inhibit kinase activity. Viability and apoptosis of cells treated with PRKCQ cDNA/shRNA/inhibitor +/-chemotherapy were measured. Expression levels of Bcl2 family members were assessed. Results: Enhanced expression of PRKCQ is sufficient to suppress apoptosis triggered by paclitaxel or doxorubicin treatment. Downregulation of PRKCQ also enhanced the apoptosis of chemotherapy-treated TNBC cells. Regulation of chemotherapy sensitivity by PRKCQ mechanistically occurs via regulation of levels of Bim, a pro-apoptotic Bcl2 family member; suppression of Bim prevents the enhanced apoptosis observed with combined PRKCQ downregulation and chemotherapy treatment. Regulation of Bim and chemotherapy sensitivity is significantly dependent on PRKCQ kinase activity; overexpression of a catalytically inactive PRKCQ does not suppress Bim or chemotherapy-associated apoptosis. Furthermore, PRKCQ kinase inhibitor treatment suppressed growth, increased anoikis and Bim expression, and enhanced apoptosis of chemotherapy-treated TNBC cells, phenocopying the effects of PRKCQ downregulation. Conclusions: These studies support PRKCQ inhibition as an attractive therapeutic strategy and complement to chemotherapy to inhibit the growth and survival of TNBC cells.

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Anoikis in cell fate, physiopathology, and therapeutic interventions

Mei,

Jiang,

Tian

et al. 2024

MedComm

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The extracellular matrix (ECM) governs a wide spectrum of cellular fate processes, with a particular emphasis on anoikis, an integrin‐dependent form of cell death. Currently, anoikis is defined as an intrinsic apoptosis. In contrast to traditional apoptosis and necroptosis, integrin correlates ECM signaling with intracellular signaling cascades, describing the full process of anoikis. However, anoikis is frequently overlooked in physiological and pathological processes as well as traditional in vitro research models. In this review, we summarized the role of anoikis in physiological and pathological processes, spanning embryonic development, organ development, tissue repair, inflammatory responses, cardiovascular diseases, tumor metastasis, and so on. Similarly, in the realm of stem cell research focused on the functional evolution of cells, anoikis offers a potential solution to various challenges, including in vitro cell culture models, stem cell therapy, cell transplantation, and engineering applications, which are largely based on the regulation of cell fate by anoikis. More importantly, the regulatory mechanisms of anoikis based on molecular processes and ECM signaling will provide new strategies for therapeutic interventions (drug therapy and cell‐based therapy) in disease. In summary, this review provides a systematic elaboration of anoikis, thus shedding light on its future research.

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PRKCQ promotes oncogenic growth and anoikis resistance of a subset of triple-negative breast cancer cells

Cited by 35 publications

References 36 publications

Analysis of Copy-Number Variations and Feline Mammary Carcinoma Survival

Analysis of Copy-Number Variations and Feline Mammary Carcinoma Survival

PRKCQ inhibition enhances chemosensitivity of triple-negative breast cancer by regulating Bim

Anoikis in cell fate, physiopathology, and therapeutic interventions

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