Tumor cell differentiation by butyrate and environmental stress
Introduction
Butyrate and its derivatives have been shown to induce differentiation in a variety of tumor cells in vitro [21] and subsequently, reports of anecdotal clinical applications and phase I pharmacokinetic studies have been published following the idea of differentiation therapy of malignant disease [3], [6], [26], [30], [31]. However, the cellular mechanisms by which butyrate exerts its effects on tumor cells leading to inhibition of cell growth, induction of differentiation markers and morphological changes into a more benign phenotype are largely unknown. Recently, activation of peroxisome proliferator-activated receptor gamma has been shown to be a target of phenylacetate and phenylbutyrate action [36]. We have previously shown that butyrate induces erythroid differentiation of K562 leukemia cells by modulation of the MAPkinase system [40]: inhibition of ERK and activation of p38 MAP kinase pathways are involved in butyrate action on K562 cells. Since p38 kinase belongs to a group of kinases known to be activated by environmental stress and therefore being referred to as stress activated protein kinases (SAPKs), we focused in the present study on the role of stress signaling in induction of differentiation of K562 erythroleukemia, PANC1 pancreatic carcinoma, HT29 colon carcinoma and HL60 promyelocytic leukemia cells.
Section snippets
Cell culture
The human erythroleukemia cell line K562, also referred to as K562s (sensitive to butyrate) in this paper was obtained from ATCC, Philadelphia, PA. The K562 subline K562r (resistant to butyrate) was purchased from DSM, Braunschweig, Germany. The human promyelocytic leukemia cell line HL60, the human pancreatic carcinoma cell line PANC1 and the human colon carcinoma cell line HT29 were obtained from CLS, Heidelberg, Germany. All cells were cultured in RPMI 1640 (12-702 Bio-Whittaker,
p38 MAP kinase inhibitor reduces butyrate-induced differentiation of tumor cells
To elucidate the role of stress signaling in induction of tumor cell differentiation by butyrate we have investigated the effect of p38-specific inhibitor SB203580 [2], [8], [22] on butyrate induced differentiation of K562, PANC1, HT29 and HL60 cells. Inhibition of p38 kinase by SB203580 reduced butyrate-mediated differentiation of K562, PANC1 and HT29 cells in a concentration-dependent manner (Fig. 1A, black bars). SB203580 alone slightly reduced basal expression of differentiation markers in
Discussion
Starting point of our experiments was the observation that butyrate-induced erythroid differentiation of K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathway [40]. Since p38 kinase belongs to a group of kinases known to be activated by environmental stress and referred to as stress activated protein kinase (SAPK), we have focused in the present study on the role of stress signaling in induction of differentiation in different tumor cell lines.
Using specific
Acknowledgements
This work was supported by a grant of the Forschungsförderungsprogramm from the Faculty of Medicine, University of Göttingen.
References (41)
- et al.
Induction of differentiation in HL-60 leukemia cells: a cell cycle dependent all-or-none event
Leukemia Res.
(1984) - et al.
SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1
FEBS Lett.
(1995) - et al.
Hsp25 and the p38 MAPK pathway are involved in differentiation of cardiomyocytes
Dev. Biol.
(2000) - et al.
Specific inhibitors of p38 mitogen-activated protein kinase block 3T3-L1 adipogenesis
J. Biol. Chem.
(1998) - et al.
Identification of a novel inhibitor of mitogen activated protein kinase kinase
J. Biol. Chem.
(1998) - et al.
Effects of sodium butyrate on human colonic adenocarcinoma cells
J. Biol. Chem.
(1987) - et al.
Differential effects of sodium butyrate and hyperosmolality on the modulation of alkaline phosphatases of LoVo cells
Exp. Cell Res.
(1990) - et al.
Specific activation of the p38 mitogen-activated protein kinase signaling pathway and induction of neurite outgrowth in PC12 cells by bone morphogenetic protein-2
J. Biol. Chem.
(1999) - et al.
Signal transduction through MAP kinase cascades
Adv. Cancer Res.
(1998) - et al.
Inhibition of heat shock factor activity prevents heat shock potentiation of glucocorticoid receptor-mediated gene expression
Cell Stress Chaperones
(1999)
Effects of sodium butyrate and dimethylsulfoxide on human pancreatic tumor cell lines
Eur. J. Cancer Clin. Oncol.
Clinical pharmacology of sodium butyrate in patients with acute leukemia
Eur. J. Cancer Clin. Oncol.
Requirement of p38 mitogen-activated protein kinase for neuronal differentiation of PC12 cells
J. Biol. Chem.
Activation of p38 MAP kinase and JNK but not ERK is required for erythropoietin-induced erythroid differentiation
Blood
Requirement of activation of JNK and p38 for environmental stress-induced erythroid differentiation and apoptosis and of inhibition of ERK for apoptosis
Blood
Butyrate induced erythroid differentiation of human K562 cells involves inhibition of ERK and activation of p38 MAP kinase-pathways
Blood
p38 mitogen-activated protein kinase pathway promotes skeletal muscle differentiation. Participation of the Mef2c transcription factor
J. Biol. Chem.
Emergence of permanently differentiated cell clones in a human colonic cancer cell line in culture after treatment with sodium butyrate
Cancer Res.
Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function
J. Pharmacol. Exp. Ther.
Plasma protein binding of phenylacetate and phenylbutyrate, two novel antineoplastic agents
Ther. Drug Monit.
Cited by (29)
The differentiation of colorectal cancer is closely relevant to m6A modification
2021, Biochemical and Biophysical Research CommunicationsCitation Excerpt :These results suggested the superposition effect may be caused by the obvious decrease of METTL3, METTL16 and WTAP, which resulted in the decrease of total m6A in DIDM. Sodium butyrate (NaBT) induction model has been reported to confirm the feasibility of its cell differentiation model construction [20, 21]. NaBT was added when the cells were nearly 80% density and samples were extracted at different time points respectively (Fig. 3A).
The proteomic study of sodium butyrate antiproliferative/cytodifferentiation effects on K562 cells
2006, Blood Cells, Molecules, and DiseasesIdentification of caffeoylquinic acid derivatives from Brazilian propolis as constituents involved in induction of granulocytic differentiation of HL-60 cells
2005, Bioorganic and Medicinal Chemistryp38 MAPK signaling pathway is involved in butyrate-induced vitamin D receptor expression
2004, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Alkaline phosphatase (AP) activity was used to measure differentiation of the investigated cells. AP activity is one of the surrogate markers of colon cell differentiation [28,29]. For the assay, attached growing cells were washed with cold phosphate buffered saline, scraped, sonicated (2 × 20 s), and centrifuged at 10,000 rpm for 10 min at 4 °C.
GAD 67KD antisense in colon cancer cells inhibits cell growth and sensitizes to butyrate and pH reduction and H <inf>2</inf>O <inf>2</inf> and γ-radiation
2004, Archives of Biochemistry and Biophysics