MDR1 up-regulated by apoptotic stimuli suppresses apoptotic signaling.
OBJECTIVE
Recently, MDR1 (P-glycoprotein) and related transporters have been suggested to play a fundamental role in regulating apoptosis, 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.


CONCLUSIONS
MDR1 is upregulated by apoptotic stimuli suppressed apoptotic signaling presumably via the mitochondrial pathway.
Sakaeda
Toshiyuki
T
Department of Hospital Pharmacy, School of Medicine, Kobe University, Japan. sakaedat@med.kobe-u.ac.jp
Nakamura
Tsutomu
T
Hirai
Midori
M
Kimura
Takashi
T
Wada
Atsushi
A
Yagami
Tatsurou
T
Kobayashi
Hironao
H
Nagata
Shunji
S
Okamura
Noboru
N
Yoshikawa
Takayoshi
T
Shirakawa
Toshiro
T
Gotoh
Akinobu
A
Matsuo
Masafumi
M
Okumura
Katsuhiko
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D002945:Cisplatin / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin