Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance

Dharminder Chauhan; Guilan Li; Teru Hideshima; Klaus Podar; Constantine Mitsiades; Nicholas Mitsiades; Laurence Catley; Yu Tzu Tai; Toshiaki Hayashi; Reshma Shringarpure; Renate Burger; Nikhil Munshi; Yasuyuki Ohtake; Satya Saxena; Kenneth C Anderson

doi:10.1182/blood-2003-05-1417

Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance

Dharminder Chauhan, Guilan Li, Teru Hideshima, Klaus Podar, Constantine Mitsiades, Nicholas Mitsiades, Laurence Catley, Yu Tzu Tai, Toshiaki Hayashi, Reshma Shringarpure, Renate Burger, Nikhil Munshi, Yasuyuki Ohtake, Satya Saxena, Kenneth C Anderson

Research output: Journal article (peer-reviewed) › Journal article

141 Citations (Scopus)

Abstract

Smac, second mitochondria-derived activator of caspases, promotes apoptosis via activation of caspases. Heat shock protein 27 (Hsp27) negatively regulates another mitochondrial protein, cytochrome c, during apoptosis; however, the role of Hsp27 in modulating Smac release is unknown. Here we show that Hsp27 is overexpressed in both dexamethasone (Dex)-resistant multiple myeloma (MM) cell lines (MM.1R, U266, RPMI-8226) and primary patient cells. Blocking Hsp27 by an antisense (AS) strategy restores the apoptotic response to Dex in Dex-resistant MM cells by triggering the release of mitochondrial protein Smac, followed by activation of caspase-9 and caspase-3. Moreover, AS-Hsp27 overcomes interleukin-6 (IL-6)-mediated protection against Dex-induced apoptosis. These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells.

Original language	English
Pages (from-to)	3379-3386
Number of pages	8
Journal	Blood
Volume	102
Issue number	9
DOIs	https://doi.org/10.1182/blood-2003-05-1417
Publication status	Published - 01 Nov 2003
Externally published	Yes

Keywords

Apoptosis/drug effects
Caspase 3
Caspase 9
Caspases/metabolism
Cell Line, Tumor
Dexamethasone/pharmacology
Drug Resistance, Neoplasm
HSP27 Heat-Shock Proteins
Heat-Shock Proteins/physiology
Humans
Immunomagnetic Separation
Interleukin-6/pharmacology
Molecular Chaperones
Multiple Myeloma/metabolism
Neoplasm Proteins/physiology
Oligonucleotides, Antisense/pharmacology
Tumor Cells, Cultured

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10.1182/blood-2003-05-1417

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Chauhan, D., Li, G., Hideshima, T., Podar, K., Mitsiades, C., Mitsiades, N., Catley, L., Tai, Y. T., Hayashi, T., Shringarpure, R., Burger, R., Munshi, N., Ohtake, Y., Saxena, S., & Anderson, K. C. (2003). Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance. Blood, 102(9), 3379-3386. https://doi.org/10.1182/blood-2003-05-1417

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title = "Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance",

abstract = "Smac, second mitochondria-derived activator of caspases, promotes apoptosis via activation of caspases. Heat shock protein 27 (Hsp27) negatively regulates another mitochondrial protein, cytochrome c, during apoptosis; however, the role of Hsp27 in modulating Smac release is unknown. Here we show that Hsp27 is overexpressed in both dexamethasone (Dex)-resistant multiple myeloma (MM) cell lines (MM.1R, U266, RPMI-8226) and primary patient cells. Blocking Hsp27 by an antisense (AS) strategy restores the apoptotic response to Dex in Dex-resistant MM cells by triggering the release of mitochondrial protein Smac, followed by activation of caspase-9 and caspase-3. Moreover, AS-Hsp27 overcomes interleukin-6 (IL-6)-mediated protection against Dex-induced apoptosis. These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells.",

keywords = "Apoptosis/drug effects, Caspase 3, Caspase 9, Caspases/metabolism, Cell Line, Tumor, Dexamethasone/pharmacology, Drug Resistance, Neoplasm, HSP27 Heat-Shock Proteins, Heat-Shock Proteins/physiology, Humans, Immunomagnetic Separation, Interleukin-6/pharmacology, Molecular Chaperones, Multiple Myeloma/metabolism, Neoplasm Proteins/physiology, Oligonucleotides, Antisense/pharmacology, Tumor Cells, Cultured",

author = "Dharminder Chauhan and Guilan Li and Teru Hideshima and Klaus Podar and Constantine Mitsiades and Nicholas Mitsiades and Laurence Catley and Tai, {Yu Tzu} and Toshiaki Hayashi and Reshma Shringarpure and Renate Burger and Nikhil Munshi and Yasuyuki Ohtake and Satya Saxena and Anderson, {Kenneth C}",

year = "2003",

month = nov,

day = "1",

doi = "10.1182/blood-2003-05-1417",

language = "English",

volume = "102",

pages = "3379--3386",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "9",

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Chauhan, D, Li, G, Hideshima, T, Podar, K, Mitsiades, C, Mitsiades, N, Catley, L, Tai, YT, Hayashi, T, Shringarpure, R, Burger, R, Munshi, N, Ohtake, Y, Saxena, S & Anderson, KC 2003, 'Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance', Blood, vol. 102, no. 9, pp. 3379-3386. https://doi.org/10.1182/blood-2003-05-1417

TY - JOUR

T1 - Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance

AU - Chauhan, Dharminder

AU - Li, Guilan

AU - Hideshima, Teru

AU - Podar, Klaus

AU - Mitsiades, Constantine

AU - Mitsiades, Nicholas

AU - Catley, Laurence

AU - Tai, Yu Tzu

AU - Hayashi, Toshiaki

AU - Shringarpure, Reshma

AU - Burger, Renate

AU - Munshi, Nikhil

AU - Ohtake, Yasuyuki

AU - Saxena, Satya

AU - Anderson, Kenneth C

PY - 2003/11/1

Y1 - 2003/11/1

N2 - Smac, second mitochondria-derived activator of caspases, promotes apoptosis via activation of caspases. Heat shock protein 27 (Hsp27) negatively regulates another mitochondrial protein, cytochrome c, during apoptosis; however, the role of Hsp27 in modulating Smac release is unknown. Here we show that Hsp27 is overexpressed in both dexamethasone (Dex)-resistant multiple myeloma (MM) cell lines (MM.1R, U266, RPMI-8226) and primary patient cells. Blocking Hsp27 by an antisense (AS) strategy restores the apoptotic response to Dex in Dex-resistant MM cells by triggering the release of mitochondrial protein Smac, followed by activation of caspase-9 and caspase-3. Moreover, AS-Hsp27 overcomes interleukin-6 (IL-6)-mediated protection against Dex-induced apoptosis. These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells.

AB - Smac, second mitochondria-derived activator of caspases, promotes apoptosis via activation of caspases. Heat shock protein 27 (Hsp27) negatively regulates another mitochondrial protein, cytochrome c, during apoptosis; however, the role of Hsp27 in modulating Smac release is unknown. Here we show that Hsp27 is overexpressed in both dexamethasone (Dex)-resistant multiple myeloma (MM) cell lines (MM.1R, U266, RPMI-8226) and primary patient cells. Blocking Hsp27 by an antisense (AS) strategy restores the apoptotic response to Dex in Dex-resistant MM cells by triggering the release of mitochondrial protein Smac, followed by activation of caspase-9 and caspase-3. Moreover, AS-Hsp27 overcomes interleukin-6 (IL-6)-mediated protection against Dex-induced apoptosis. These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells.

KW - Apoptosis/drug effects

KW - Caspase 3

KW - Caspase 9

KW - Caspases/metabolism

KW - Cell Line, Tumor

KW - Dexamethasone/pharmacology

KW - Drug Resistance, Neoplasm

KW - HSP27 Heat-Shock Proteins

KW - Heat-Shock Proteins/physiology

KW - Humans

KW - Immunomagnetic Separation

KW - Interleukin-6/pharmacology

KW - Molecular Chaperones

KW - Multiple Myeloma/metabolism

KW - Neoplasm Proteins/physiology

KW - Oligonucleotides, Antisense/pharmacology

KW - Tumor Cells, Cultured

UR - http://www.scopus.com/inward/record.url?scp=0142245588&partnerID=8YFLogxK

U2 - 10.1182/blood-2003-05-1417

DO - 10.1182/blood-2003-05-1417

M3 - Journal article

C2 - 12855565

SN - 0006-4971

VL - 102

SP - 3379

EP - 3386

JO - Blood

JF - Blood

IS - 9

ER -

Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance

Abstract

Keywords

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