Increased expression of cdc2 inhibits transport function of RLIP76 and promotes apoptosis

Sharad S. Singhal; Sushma Yadav; Rit Vatsyayan; Pankaj Chaudhary; Jozef Borvak; Jyotsana Singhal; Sanjay Awasthi

doi:10.1016/j.canlet.2009.03.033

Increased expression of cdc2 inhibits transport function of RLIP76 and promotes apoptosis

Sharad S. Singhal, Sushma Yadav, Rit Vatsyayan, Pankaj Chaudhary, Jozef Borvak, Jyotsana Singhal, Sanjay Awasthi

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

RLIP76 is a stress-responsive glutathione-electrophile-conjugates (GS-E) and drugs transporter which is over-expressed in different types of cancers. Cdc2 is a cell-cycle check point control kinase which has been shown to bind to RLIP76 during mitosis, such that endocytosis is inhibited. In present studies, we have purified cdc2 and examined its effect on the transport activity of RLIP76 reconstituted into artificial liposomes. Both doxorubicin (DOX) and dinitro-phenyl S-glutathione (DNP-SG) transport were inhibited by cdc2 in a concentration dependent manner. Liposomal delivery of cdc2 to H358 cells caused apoptosis, resulted in an increased intracellular doxorubicin-accumulation and decreased rate of efflux from the cells. In the present communication, we propose that the accumulation-deficient drug-resistance mediated by RLIP76 can be modulated by inhibition of RLIP76 transport activity by cdc2.

Original language	English
Pages (from-to)	152-158
Number of pages	7
Journal	Cancer Letters
Volume	283
Issue number	2
DOIs	https://doi.org/10.1016/j.canlet.2009.03.033
State	Published - 8 Oct 2009

Keywords

Apoptosis
Cdc2
Doxorubicin
Drug-resistance
Glutathione-conjugate
RLIP76
Transport inhibition

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10.1016/j.canlet.2009.03.033

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title = "Increased expression of cdc2 inhibits transport function of RLIP76 and promotes apoptosis",

abstract = "RLIP76 is a stress-responsive glutathione-electrophile-conjugates (GS-E) and drugs transporter which is over-expressed in different types of cancers. Cdc2 is a cell-cycle check point control kinase which has been shown to bind to RLIP76 during mitosis, such that endocytosis is inhibited. In present studies, we have purified cdc2 and examined its effect on the transport activity of RLIP76 reconstituted into artificial liposomes. Both doxorubicin (DOX) and dinitro-phenyl S-glutathione (DNP-SG) transport were inhibited by cdc2 in a concentration dependent manner. Liposomal delivery of cdc2 to H358 cells caused apoptosis, resulted in an increased intracellular doxorubicin-accumulation and decreased rate of efflux from the cells. In the present communication, we propose that the accumulation-deficient drug-resistance mediated by RLIP76 can be modulated by inhibition of RLIP76 transport activity by cdc2.",

keywords = "Apoptosis, Cdc2, Doxorubicin, Drug-resistance, Glutathione-conjugate, RLIP76, Transport inhibition",

author = "Singhal, {Sharad S.} and Sushma Yadav and Rit Vatsyayan and Pankaj Chaudhary and Jozef Borvak and Jyotsana Singhal and Sanjay Awasthi",

note = "Funding Information: This study was supported in part by NIH Grants CA 77495 and CA 104661, Cancer Research Foundation of North Texas, Institute for Cancer Research and the Joe & Jessie Crump Fund for Medical Education.",

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doi = "10.1016/j.canlet.2009.03.033",

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AU - Singhal, Sharad S.

AU - Yadav, Sushma

AU - Vatsyayan, Rit

AU - Chaudhary, Pankaj

AU - Borvak, Jozef

AU - Singhal, Jyotsana

AU - Awasthi, Sanjay

N1 - Funding Information: This study was supported in part by NIH Grants CA 77495 and CA 104661, Cancer Research Foundation of North Texas, Institute for Cancer Research and the Joe & Jessie Crump Fund for Medical Education.

PY - 2009/10/8

Y1 - 2009/10/8

N2 - RLIP76 is a stress-responsive glutathione-electrophile-conjugates (GS-E) and drugs transporter which is over-expressed in different types of cancers. Cdc2 is a cell-cycle check point control kinase which has been shown to bind to RLIP76 during mitosis, such that endocytosis is inhibited. In present studies, we have purified cdc2 and examined its effect on the transport activity of RLIP76 reconstituted into artificial liposomes. Both doxorubicin (DOX) and dinitro-phenyl S-glutathione (DNP-SG) transport were inhibited by cdc2 in a concentration dependent manner. Liposomal delivery of cdc2 to H358 cells caused apoptosis, resulted in an increased intracellular doxorubicin-accumulation and decreased rate of efflux from the cells. In the present communication, we propose that the accumulation-deficient drug-resistance mediated by RLIP76 can be modulated by inhibition of RLIP76 transport activity by cdc2.

AB - RLIP76 is a stress-responsive glutathione-electrophile-conjugates (GS-E) and drugs transporter which is over-expressed in different types of cancers. Cdc2 is a cell-cycle check point control kinase which has been shown to bind to RLIP76 during mitosis, such that endocytosis is inhibited. In present studies, we have purified cdc2 and examined its effect on the transport activity of RLIP76 reconstituted into artificial liposomes. Both doxorubicin (DOX) and dinitro-phenyl S-glutathione (DNP-SG) transport were inhibited by cdc2 in a concentration dependent manner. Liposomal delivery of cdc2 to H358 cells caused apoptosis, resulted in an increased intracellular doxorubicin-accumulation and decreased rate of efflux from the cells. In the present communication, we propose that the accumulation-deficient drug-resistance mediated by RLIP76 can be modulated by inhibition of RLIP76 transport activity by cdc2.

KW - Apoptosis

KW - Cdc2

KW - Doxorubicin

KW - Drug-resistance

KW - Glutathione-conjugate

KW - RLIP76

KW - Transport inhibition

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DO - 10.1016/j.canlet.2009.03.033

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SN - 0304-3835

VL - 283

SP - 152

EP - 158

JO - Cancer Letters

JF - Cancer Letters

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ER -

Increased expression of cdc2 inhibits transport function of RLIP76 and promotes apoptosis

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