Cancer Letters

Cancer Letters

Volume 171, Issue 2, 10 October 2001, Pages 173-182
Cancer Letters

Tumor cell differentiation by butyrate and environmental stress

https://doi.org/10.1016/S0304-3835(01)00628-0Get rights and content

Abstract

The present study shows that stress signaling plays a role in differentiation of K562, PANC1, HT29 and HL60 tumor cells: (1) Butyrate induced differentiation in K562, PANC1, and HT29 cells can be inhibited by SB203580, a specific inhibitor of p38 stress activated protein kinase. (2) Heat shock and hyperosmolarity increase expression of differentiation markers in K562, HT29, HL60 and in K562, PANC1, and HT29 cells, respectively. (3) Conversely, environmental stress induced differentiation in K562, HT29, and PANC1 cells can be inhibited by SB203580 and quercetin, a compound with heat shock pathway inhibiting activity. (4) Butyrate and environmental stress enhance either additively or synergistically differentiation of K562, HT29, PANC1 or HL60 cells, respectively. Stress signaling pathways might be an interesting pharmacologic target for differentiation therapy of malignant disease.

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.

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