Downregulation of Choline Kinase-Alpha Enhances Autophagy in Tamoxifen-Resistant Breast Cancer Cells

Kim, Hoe Suk; Tian, Lianji; Jung, Minji; Choi, Sul Ki; Sun, Yujin; Kim, Hyeonjin; Moon, Woo Kyung

doi:10.1371/journal.pone.0141110

Cited by 15 publications

(11 citation statements)

References 47 publications

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“…EBSS and 3-MA co-treatment further decreased cell viabilities in both cell lines, and there was no significant difference between CHO/CTRL and CHO/SP1 (Figure 6B). Although 3-MA inhibits autophagy process in cells, it was previously reported that 3-MA treatment itself induced apoptosis without autophagy [51,52]. The entire blockade of autophagy in cells rather caused apoptosis, even in the absence of starvation.…”

Section: Resultsmentioning

confidence: 99%

Silkworm Storage Protein 1 Inhibits Autophagy-Mediated Apoptosis

Kang

Rhee

2019

IJMS

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Autophagy is a natural physiological process, and it induces the lysosomal degradation of intracellular components in response to environmental stresses, including nutrient starvation. Although an adequate autophagy level helps in cell survival, excessive autophagy triggered by stress such as starvation leads to autophagy-mediated apoptosis. Chinese hamster ovary (CHO) cells are widely used for producing biopharmaceuticals, including monoclonal antibodies. However, apoptosis induced by high stress levels, including nutrient deficiency, is a major problem in cell cultures grown in bioreactors, which should be overcome. Therefore, it is necessary to develop a method for suppressing excessive autophagy and for maintaining an appropriate autophagy level in cells. Therefore, we investigated the effect of silkworm storage protein 1 (SP1), an antiapoptotic protein, on autophagy-mediated apoptosis. SP1-expressing CHO cells were generated to assess the effect and molecular mechanism of SP1 in suppressing autophagy. These cells were cultured under starvation conditions by treatment with Earle’s balanced salt solution (EBSS) to induce autophagy. We observed that SP1 significantly inhibited autophagy-mediated apoptosis by suppressing caspase-3 activation and reactive oxygen species generation. In addition, SP1 suppressed EBSS-induced conversion of LC3-I to LC3-II and the expression of autophagy-related protein 7. Notably, basal Beclin-1 level was significantly low in the SP1-expressing cells, indicating that SP1 regulated upstream events in the autophagy pathway. Together, these findings suggest that SP1 offers a new strategy for overcoming severe autophagy-mediated apoptosis in mammalian cells, and it can be used widely in biopharmaceutical production.

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Section: Resultsmentioning

confidence: 99%

Silkworm Storage Protein 1 Inhibits Autophagy-Mediated Apoptosis

Kang

Rhee

2019

IJMS

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“…Although it has anti-estrogen activity, TAM is widely used to treat ER-positive breast tumors as an adjuvant therapy for early-stage hormone-sensitive breast cancer or first line therapy for metastatic hormone-sensitive breast cancer, and as many as 30% of patients can be refractory to TAM and acquire resistance to TAM along with the loss of ER-α [ 6 , 22 – 24 ]. CK-α is one of the targets of therapeutic strategies because it is a key enzyme in choline metabolism and might contribute to TAM resistance [ 11 , 19 ]. In addition, the metabolic survival-promotion function of autophagy, which is activated in drug resistant BCCs, is also one of the therapeutic targets [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…CK-α is one of the targets of therapeutic strategies because it is a key enzyme in choline metabolism and might contribute to TAM resistance [ 11 , 19 ]. In addition, the metabolic survival-promotion function of autophagy, which is activated in drug resistant BCCs, is also one of the therapeutic targets [ 19 ]. Our recent study reported a potential connection between autophagy and CK-α in the mechanisms driving TAM resistance in ER+ BCCs.…”

Section: Discussionmentioning

confidence: 99%

“…New targeted biomarkers are needed to improve the prognosis for TAM-resistant BC patients. Recently, we reported that CK-α knockdown promoted autophagy induction for survival and dormancy of TAM-resistant and CK-α-knockdown BCCs [ 19 ]. Therefore, the discriminant metabolites altered by CK-α knockdown and TAM resistance may allow us to understand the properties of breast cancer cells related to promoting autophagy and TAM resistance.…”

Section: Introductionmentioning

confidence: 99%

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Investigation of discriminant metabolites in tamoxifen-resistant and choline kinase-alpha-downregulated breast cancer cells using 1H-nuclear magnetic resonance spectroscopy

et al. 2017

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Metabolites linked to changes in choline kinase-α (CK-α) expression and drug resistance, which contribute to survival and autophagy mechanisms, are attractive targets for breast cancer therapies. We previously reported that autophagy played a causative role in driving tamoxifen (TAM) resistance of breast cancer cells (BCCs) and was also promoted by CK-α knockdown, resulting in the survival of TAM-resistant BCCs. There is no comparative study yet about the metabolites resulting from BCCs with TAM-resistance and CK-α knockdown. Therefore, the aim of this study was to explore the discriminant metabolic biomarkers responsible for TAM resistance as well as CK-α expression, which might be linked with autophagy through a protective role. A total of 33 intracellular metabolites, including a range of amino acids, energy metabolism-related molecules and others from cell extracts of the parental cells (MCF-7), TAM-resistant cells (MCF-7/TAM) and CK-α knockdown cells (MCF-7/shCK-α, MCF-7/TAM/shCK-α) were analyzed by proton nuclear magnetic resonance spectroscopy (1H-NMRS). Principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA) revealed the existence of differences in the intracellular metabolites to separate the 4 groups: MCF-7 cells, MCF-7/TAM cells, MCF-7-shCK-α cells, and MCF-7/TAM/shCK-α cells. The metabolites with VIP>1 contributed most to the differentiation of the cell groups, and they included fumarate, UA (unknown A), lactate, myo-inositol, glycine, phosphocholine, UE (unknown E), glutamine, formate, and AXP (AMP/ADP/ATP). Our results suggest that these altered metabolites would be promising metabolic biomarkers for a targeted therapeutic strategy in BCCs that exhibit TAM-resistance and aberrant CK-α expression, which triggers a survival and drug resistance mechanism.

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“…Overexpression of the CHKα protein can transform noncancerous cells into cells with a cancerous phenotype, and conversely, knockdown of the CHKα protein by siRNA can result in cancer cell death [14]. It has also been shown that siRNA mediated knockdown of CHKA results in upregulation of autophagy, which was further associated with a reduction in cell proliferation in breast cancer cell lines [15]. The precise molecular mechanism underlying this link between choline metabolism and autophagy is unclear.…”

Section: The Role Of Chkαmentioning

confidence: 99%

Molecular structure and differential function of choline kinases CHKα and CHKβ in musculoskeletal system and cancer

Chen

Qiu

Wang

et al. 2017

Cytokine & Growth Factor Reviews

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Choline, a hydrophilic cation, has versatile physiological roles throughout the body, including cholinergic neurotransmission, memory consolidation and membrane biosynthesis and metabolism. Choline kinases possess enzyme activity that catalyses the conversion of choline to phosphocholine, which is further converted to cytidine diphosphate-coline (CDP-choline) in the biosynthesis of phosphatidylcholine (PC). PC is a major constituent of the phospholipid bilayer which constitutes the eukaryotic cell membrane, and regulates cell signal transduction. Choline Kinase consists of three isoforms, CHKα1, CHKα2 and CHKβ, encoded by two separate genes (CHKA(Human)/Chka(Mouse) and CHKB(Human)/Chkb(Mouse)). Both isoforms have similar structures and enzyme activity, but display some distinct molecular structural domains and differential tissue expression patterns. Whilst Choline Kinase was discovered in early 1950, its pivotal role in the development of muscular dystrophy, bone deformities, and cancer has only recently been identified. CHKα has been proposed as a cancer biomarker and its inhibition as an anti-cancer therapy. In contrast, restoration of CHKβ deficiency through CDP-choline supplements like citicoline may be beneficial for the treatment of muscular dystrophy, bone metabolic diseases, and cognitive conditions. The molecular structure and expression pattern of Choline Kinase, the differential roles of Choline Kinase isoforms and their potential as novel therapeutic targets for muscular dystrophy, bone deformities, cognitive conditions and cancer are discussed.

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Downregulation of Choline Kinase-Alpha Enhances Autophagy in Tamoxifen-Resistant Breast Cancer Cells

Cited by 15 publications

References 47 publications

Silkworm Storage Protein 1 Inhibits Autophagy-Mediated Apoptosis

Silkworm Storage Protein 1 Inhibits Autophagy-Mediated Apoptosis

Investigation of discriminant metabolites in tamoxifen-resistant and choline kinase-alpha-downregulated breast cancer cells using 1H-nuclear magnetic resonance spectroscopy

Molecular structure and differential function of choline kinases CHKα and CHKβ in musculoskeletal system and cancer

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