PMID- 22710939
OWN - NLM
STAT- MEDLINE
DCOM- 20130117
LR  - 20211021
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 82
IP  - 3
DP  - 2012 Sep
TI  - Sec61beta controls sensitivity to platinum-containing chemotherapeutic agents 
      through modulation of the copper-transporting ATPase ATP7A.
PG  - 510-20
LID - 10.1124/mol.112.079822 [doi]
AB  - The Sec61 protein translocon is a multimeric complex that transports proteins 
      across lipid bilayers. We discovered that the Sec61beta subunit modulates cellular 
      sensitivity to chemotherapeutic agents, particularly the platinum drugs. To 
      investigate the mechanism, expression of Sec61beta was constitutively knocked down 
      in 2008 ovarian cancer cells. Sec61beta knockdown (KD) resulted in 8-, 16.8-, and 
      9-fold resistance to cisplatin (cDDP), carboplatin, and oxaliplatin, 
      respectively. Sec61beta KD reduced the cellular accumulation of cDDP to 67% of that 
      in parental cells. Baseline copper levels, copper uptake, and copper cytotoxicity 
      were also reduced. Because copper transporters and chaperones regulate platinum 
      drug accumulation and efflux, their expression in 2008 Sec61beta-KD cells was 
      analyzed; ATP7A was found to be 2- to 3-fold overexpressed, whereas there was no 
      change in ATP7B, ATOX1, CTR1, or CTR2 levels. Cells lacking ATP7A did not exhibit 
      increased cDDP resistance upon knockdown of Sec61beta. Sec61beta-KD cells also 
      exhibited altered ATP7A cellular distribution. We conclude that Sec61beta modulates 
      the cytotoxicity of many chemotherapeutic agents, with the largest effect being 
      on the platinum drugs. This modulation occurs through effects of Sec61beta on the 
      expression and distribution of ATP7A, which was shown previously to control 
      platinum drug sequestration and cytotoxicity.
FAU - Abada, Paolo B
AU  - Abada PB
AD  - Moores UCSD Cancer Center, La Jolla, CA 92093-0819, USA. pabada@ucsd.edu
FAU - Larson, Christopher A
AU  - Larson CA
FAU - Manorek, Gerald
AU  - Manorek G
FAU - Adams, Preston
AU  - Adams P
FAU - Howell, Stephen B
AU  - Howell SB
LA  - eng
GR  - T32 CA121938/CA/NCI NIH HHS/United States
GR  - CA095298/CA/NCI NIH HHS/United States
GR  - R01 CA152185/CA/NCI NIH HHS/United States
GR  - CA152185/CA/NCI NIH HHS/United States
GR  - R01 CA095298/CA/NCI NIH HHS/United States
GR  - T32-CA121938/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120618
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cation Transport Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Organoplatinum Compounds)
RN  - 0 (SEC Translocation Channels)
RN  - 0 (SEC61B protein, human)
RN  - 789U1901C5 (Copper)
RN  - EC 3.6.1.- (Adenosine Triphosphatases)
RN  - EC 7.2.2.8 (ATP7A protein, human)
RN  - EC 7.2.2.8 (Copper-Transporting ATPases)
SB  - IM
MH  - Adenosine Triphosphatases/genetics/*metabolism
MH  - Antineoplastic Agents/*pharmacology
MH  - Biological Transport/drug effects
MH  - Cation Transport Proteins/genetics/*metabolism
MH  - Copper/adverse effects
MH  - Copper-Transporting ATPases
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Homeostasis/drug effects
MH  - Humans
MH  - Membrane Proteins/genetics/*metabolism
MH  - Organoplatinum Compounds/*pharmacology
MH  - Ovarian Neoplasms/drug therapy/genetics/metabolism
MH  - SEC Translocation Channels
MH  - Tumor Cells, Cultured
PMC - PMC3422700
EDAT- 2012/06/20 06:00
MHDA- 2013/01/18 06:00
PMCR- 2013/09/01
CRDT- 2012/06/20 06:00
PHST- 2012/06/20 06:00 [entrez]
PHST- 2012/06/20 06:00 [pubmed]
PHST- 2013/01/18 06:00 [medline]
PHST- 2013/09/01 00:00 [pmc-release]
AID - mol.112.079822 [pii]
AID - 3790621 [pii]
AID - 10.1124/mol.112.079822 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2012 Sep;82(3):510-20. doi: 10.1124/mol.112.079822. Epub 2012 Jun 
      18.