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MDR1 Up-Regulated by Apoptotic Stimuli Suppresses Apoptotic Signaling

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Abstract

Purpose. Recently, MDR1 (P-glycoprotein) and related transporters have been suggested to play a fundamental role in regulating apo- ptosis, but little information is available concerning the role of MDR1. Here, the effect of apoptotic stimuli on the MDR1 mRNA and apoptotic signaling was examined in MDR1-overexpressing cells.

Methods. The expression levels of mRNA for MDR1, MRP1, MRP2, p53, p21, Bax, and Bcl-2 were measured by real time quantitative polymerase chain reaction in HeLa and its MDR1-overexpressing sublines. The effects of apoptotic stimuli by cisplatin (CDDP) on their levels were also assessed as well as on caspase 3, 8, and 9 activities.

Results. MDR1 was rapidly upregulated when the cells were exposed to apoptotic stimuli by CDDP. The increase in Bax mRNA to Bcl-2 mRNA ratio after treatment with CDDP was suppressed in MDR1-overexpressing cells. The increases in caspase 3 and 9 activities after treatment with CDDP were suppressed in MDR1-overexpression cells.

Conclusion. MDR1 is upregulated by apoptotic stimuli suppressed apoptotic signaling presumably via the mitochondrial pathway.

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Authors and Affiliations

  1. Department of Hospital Pharmacy, School of Medicine, Kobe University, Kobe, 650-0017, Japan

    Toshiyuki Sakaeda, Tsutomu Nakamura & Katsuhiko Okumura

  2. Department of Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, 658-8558, Japan

    Midori Hirai, Takashi Kimura & Atsushi Wada

  3. Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, 553-0002, Japan

    Tatsurou Yagami, Hironao Kobayashi, Shunji Nagata, Noboru Okamura & Takayoshi Yoshikawa

  4. Department of Urology, School of Medicine, Kobe University, Kobe, 650-0017, Japan

    Toshiro Shirakawa & Akinobu Gotoh

  5. Department of Clinical Genetics and International Center for Medical Research, School of Medicine, Kobe University, Kobe 650-0017, Japan

    Toshiro Shirakawa, Akinobu Gotoh & Masafumi Matsuo

Authors
  1. Toshiyuki Sakaeda
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  2. Tsutomu Nakamura
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Correspondence to Toshiyuki Sakaeda.

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Sakaeda, T., Nakamura, T., Hirai, M. et al. MDR1 Up-Regulated by Apoptotic Stimuli Suppresses Apoptotic Signaling. Pharm Res 19, 1323–1329 (2002). https://doi.org/10.1023/A:1020302825511

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  • DOI: https://doi.org/10.1023/A:1020302825511

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