Assessing the contribution of the two protein disulfide isomerases PDIA1 and PDIA3 to cisplatin resistance
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Assessing the contribution of the two protein disulfide isomerases PDIA1 and PDIA3 to cisplatin resistance. / Kullmann, Maximilian; Kalayda, Ganna V; Hellwig, Malte; Kotz, Sandra; Hilger, Ralf A; Metzger, Sabine; Jaehde, Ulrich.
in: J INORG BIOCHEM, Jahrgang 153, 12.2015, S. 247-252.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Assessing the contribution of the two protein disulfide isomerases PDIA1 and PDIA3 to cisplatin resistance
AU - Kullmann, Maximilian
AU - Kalayda, Ganna V
AU - Hellwig, Malte
AU - Kotz, Sandra
AU - Hilger, Ralf A
AU - Metzger, Sabine
AU - Jaehde, Ulrich
N1 - Copyright © 2015 Elsevier Inc. All rights reserved.
PY - 2015/12
Y1 - 2015/12
N2 - Intracellular binding of cisplatin to non-DNA partners, such as proteins, has received increasing attention as an additional mode of action and as mechanism of resistance. We investigated two cisplatin-interacting isoforms of protein disulfide isomerase regarding their contribution to acquired cisplatin resistance using sensitive and resistant A2780/A2780cis ovarian cancer cells. Cisplatin cytotoxicity was assessed after knockdown of either protein disulfide isomerase family A member 1 (PDIA1) or protein disulfide isomerase family A member 3 (PDIA3). Whereas PDIA1 knockdown led to increased cytotoxicity in resistant A2780cis cells, PDIA3 knockdown showed no influence on cytotoxicity. Coincubation with propynoic acid carbamoyl methyl amide 31 (PACMA31), a PDIA1 inhibitor, resensitized A2780cis cells to cisplatin treatment. Determination of the combination index revealed that the combination of cisplatin and PACMA31 acts synergistically. Our results warrant further evaluation of PDIA1 as promising target for chemotherapy, and its inhibition by PACMA31 as a new therapeutic approach.
AB - Intracellular binding of cisplatin to non-DNA partners, such as proteins, has received increasing attention as an additional mode of action and as mechanism of resistance. We investigated two cisplatin-interacting isoforms of protein disulfide isomerase regarding their contribution to acquired cisplatin resistance using sensitive and resistant A2780/A2780cis ovarian cancer cells. Cisplatin cytotoxicity was assessed after knockdown of either protein disulfide isomerase family A member 1 (PDIA1) or protein disulfide isomerase family A member 3 (PDIA3). Whereas PDIA1 knockdown led to increased cytotoxicity in resistant A2780cis cells, PDIA3 knockdown showed no influence on cytotoxicity. Coincubation with propynoic acid carbamoyl methyl amide 31 (PACMA31), a PDIA1 inhibitor, resensitized A2780cis cells to cisplatin treatment. Determination of the combination index revealed that the combination of cisplatin and PACMA31 acts synergistically. Our results warrant further evaluation of PDIA1 as promising target for chemotherapy, and its inhibition by PACMA31 as a new therapeutic approach.
KW - Antineoplastic Agents/chemistry
KW - Cell Line, Tumor
KW - Cisplatin/chemistry
KW - Drug Resistance, Neoplasm
KW - Enzyme Inhibitors/pharmacology
KW - Humans
KW - Procollagen-Proline Dioxygenase/antagonists & inhibitors
KW - Protein Binding
KW - Protein Disulfide-Isomerases/antagonists & inhibitors
U2 - 10.1016/j.jinorgbio.2015.08.028
DO - 10.1016/j.jinorgbio.2015.08.028
M3 - SCORING: Journal article
C2 - 26364260
VL - 153
SP - 247
EP - 252
JO - J INORG BIOCHEM
JF - J INORG BIOCHEM
SN - 0162-0134
ER -