Induction of multidrug resistance proteins MRP1 and MRP3 and γ-glutamylcysteine synthetase gene expression by nonsteroidal anti-inflammatory drugs in human colon cancer cells

Shigeru Tatebe, Frank A Sinicrope, M. Tien Kuo

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Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been demonstrated to suppress colorectal tumorigenesis. NSAIDs have also been used to treat inflammatory illnesses. However, the underlying mechanisms of action by NSAIDs have not been completely elucidated. In this study, we reported that among the six members of the multidrug resistance protein gene (MRP1 to MRP6) family which encode membrane transporters for a diverse group of antitumor agents, expression of MRP1 and MRP3 but not the others in human colorectal cancer cell lines was induced by sulindac. This induction profile is consistent with the results using prooxidants which produce reactive oxygen species (ROS) and generate oxidative stress as previously reported. Moreover, treatment of colorectal cancer cells with sulindac induced ROS. Suppression of ROS formation by antioxidant N-acetylcysteine (NAC) downregulated the induction of MRP1 and MRP3 expression. Expression of another oxidative stress-sensitive gene, γ-glutamylcysteine synthetase heavy subunit gene (γ-GCSh), which encodes the rate-limiting enzyme in glutathione biosynthesis, was also induced by sulindac. However, the suppression of sulindac-induced γ-GCSh expression by NAC was less sensitive compared with that of MRP1 and MRP3. We also demonstrated that induction of MRP3 and γ-GCSh was independent of intracellular COX-2 levels. These results, collectively, suggest a ROS-related, COX-2-independent mechanism for the induction of drug resistance gene expression that bears important implications to the roles of NSAIDs in colorectal carcinogenesis and inflammatory response.

Original languageEnglish (US)
Pages (from-to)1427-1433
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume290
Issue number5
DOIs
StatePublished - 2002

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Sulindac
Glutamate-Cysteine Ligase
P-Glycoproteins
Gene expression
Colonic Neoplasms
Reactive Oxygen Species
Anti-Inflammatory Agents
Cells
Gene Expression
Acetylcysteine
Oxidative stress
Pharmaceutical Preparations
Genes
Colorectal Neoplasms
Carcinogenesis
Oxidative Stress
MDR Genes
Membrane Transport Proteins
Drug Resistance
Antineoplastic Agents

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

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title = "Induction of multidrug resistance proteins MRP1 and MRP3 and γ-glutamylcysteine synthetase gene expression by nonsteroidal anti-inflammatory drugs in human colon cancer cells",
abstract = "Nonsteroidal anti-inflammatory drugs (NSAIDs) have been demonstrated to suppress colorectal tumorigenesis. NSAIDs have also been used to treat inflammatory illnesses. However, the underlying mechanisms of action by NSAIDs have not been completely elucidated. In this study, we reported that among the six members of the multidrug resistance protein gene (MRP1 to MRP6) family which encode membrane transporters for a diverse group of antitumor agents, expression of MRP1 and MRP3 but not the others in human colorectal cancer cell lines was induced by sulindac. This induction profile is consistent with the results using prooxidants which produce reactive oxygen species (ROS) and generate oxidative stress as previously reported. Moreover, treatment of colorectal cancer cells with sulindac induced ROS. Suppression of ROS formation by antioxidant N-acetylcysteine (NAC) downregulated the induction of MRP1 and MRP3 expression. Expression of another oxidative stress-sensitive gene, γ-glutamylcysteine synthetase heavy subunit gene (γ-GCSh), which encodes the rate-limiting enzyme in glutathione biosynthesis, was also induced by sulindac. However, the suppression of sulindac-induced γ-GCSh expression by NAC was less sensitive compared with that of MRP1 and MRP3. We also demonstrated that induction of MRP3 and γ-GCSh was independent of intracellular COX-2 levels. These results, collectively, suggest a ROS-related, COX-2-independent mechanism for the induction of drug resistance gene expression that bears important implications to the roles of NSAIDs in colorectal carcinogenesis and inflammatory response.",
author = "Shigeru Tatebe and Sinicrope, {Frank A} and Kuo, {M. Tien}",
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T1 - Induction of multidrug resistance proteins MRP1 and MRP3 and γ-glutamylcysteine synthetase gene expression by nonsteroidal anti-inflammatory drugs in human colon cancer cells

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AU - Kuo, M. Tien

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N2 - Nonsteroidal anti-inflammatory drugs (NSAIDs) have been demonstrated to suppress colorectal tumorigenesis. NSAIDs have also been used to treat inflammatory illnesses. However, the underlying mechanisms of action by NSAIDs have not been completely elucidated. In this study, we reported that among the six members of the multidrug resistance protein gene (MRP1 to MRP6) family which encode membrane transporters for a diverse group of antitumor agents, expression of MRP1 and MRP3 but not the others in human colorectal cancer cell lines was induced by sulindac. This induction profile is consistent with the results using prooxidants which produce reactive oxygen species (ROS) and generate oxidative stress as previously reported. Moreover, treatment of colorectal cancer cells with sulindac induced ROS. Suppression of ROS formation by antioxidant N-acetylcysteine (NAC) downregulated the induction of MRP1 and MRP3 expression. Expression of another oxidative stress-sensitive gene, γ-glutamylcysteine synthetase heavy subunit gene (γ-GCSh), which encodes the rate-limiting enzyme in glutathione biosynthesis, was also induced by sulindac. However, the suppression of sulindac-induced γ-GCSh expression by NAC was less sensitive compared with that of MRP1 and MRP3. We also demonstrated that induction of MRP3 and γ-GCSh was independent of intracellular COX-2 levels. These results, collectively, suggest a ROS-related, COX-2-independent mechanism for the induction of drug resistance gene expression that bears important implications to the roles of NSAIDs in colorectal carcinogenesis and inflammatory response.

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