Glucose restriction induces cell death in parental but not in homeodomain-interacting protein kinase 2-depleted RKO colon cancer cells: molecular mechanisms and implications for tumor therapy

Tumor cell tolerance to nutrient deprivation can be an important factor for tumor progression, and may depend on deregulation of both oncogenes and oncosuppressor proteins. Homeodomain-interacting protein kinase 2 (HIPK2) is an oncosuppressor that, following its activation by several cellular stress...

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Published in:	Cell death & disease Vol. 4; no. 5; p. e639
Main Authors:	Garufi, A, Ricci, A, Trisciuoglio, D, Iorio, E, Carpinelli, G, Pistritto, G, Cirone, M, D′Orazi, G
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-05-2013 Springer Nature B.V Nature Publishing Group
Subjects:	631/67/1504/1885/1393 631/67/2327 631/80/82 692/700/565/2072 Antibodies Apoptosis - drug effects Biochemistry Biomedical and Life Sciences Carrier Proteins - antagonists & inhibitors Carrier Proteins - genetics Carrier Proteins - metabolism Cell Biology Cell Culture Cell Line, Tumor Colonic Neoplasms - drug therapy Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Deoxyglucose - pharmacology Deoxyglucose - therapeutic use Glucose Transporter Type 1 - antagonists & inhibitors Glucose Transporter Type 1 - genetics Glucose Transporter Type 1 - metabolism Humans Immunology JNK Mitogen-Activated Protein Kinases - metabolism Life Sciences Metabolome Original original-article Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism RNA Interference RNA, Small Interfering - metabolism Zinc - pharmacology glucose zinc supplementation autophagy cell death tumor HIPK2
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Summary:	Tumor cell tolerance to nutrient deprivation can be an important factor for tumor progression, and may depend on deregulation of both oncogenes and oncosuppressor proteins. Homeodomain-interacting protein kinase 2 (HIPK2) is an oncosuppressor that, following its activation by several cellular stress, induces cancer cell death via p53-dependent or -independent pathways. Here, we used genetically matched human RKO colon cancer cells harboring wt-HIPK2 (HIPK2 +/+ ) or stable HIPK2 siRNA interference (siHIPK2) to investigate in vitro whether HIPK2 influenced cell death in glucose restriction. We found that glucose starvation induced cell death, mainly due to c-Jun NH2-terminal kinase activation, in HIPK2 +/+ cells compared with siHIPK2 cells that did not die. 1 H-nuclear magnetic resonance quantitative metabolic analyses showed a marked glycolytic activation in siHIPK2 cells. However, treatment with glycolysis inhibitor 2-deoxy- D -glucose induced cell death only in HIPK2 +/+ cells but not in siHIPK2 cells. Similarly, siGlut-1 interference did not re-establish siHIPK2 cell death under glucose restriction, whereas marked cell death was reached only after zinc supplementation, a condition known to reactivate misfolded p53 and inhibit the pseudohypoxic phenotype in this setting. Further siHIPK2 cell death was reached with zinc in combination with autophagy inhibitor. We propose that the metabolic changes acquired by cells after HIPK2 silencing may contribute to induce resistance to cell death in glucose restriction condition, and therefore be directly relevant for tumor progression. Moreover, elimination of such a tolerance might serve as a new strategy for cancer therapy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-4889 2041-4889
DOI:	10.1038/cddis.2013.163