Identification of thioredoxin-interacting protein 1 as a hypoxia-inducible factor 1alpha-induced gene in pancreatic cancer.
OBJECTIVE
To investigate the expression of thioredoxin-interacting protein (TXNIP) during hypoxia and its dependency on hypoxia-inducible factor 1alpha (HIF-1alpha) in pancreatic cancer cell lines.


METHODS
MiaPaCa-2 pancreatic cancer cells were transiently transfected with siRNA to HIF-1alpha and TXNIP protein measured after growth in normoxia or hypoxia. In addition, HIF-1alpha dependency was assessed by transiently transfecting MiaPaCa-2 pancreatic cancer cells with HIF-1alpha with a mutated oxygen degradation domain resulting in stable HIF-1alpha expression in normoxic conditions. Panc-1 pancreatic cancer cells with low endogenous TXNIP expression were stably transfected with TXNIP, and cell survival and response to platinum cancer agents were tested. Quantitative immunohistochemistry was utilized to measure the expression of TXNIP and thioredoxin 1 in human pancreatic cancer tissues.


RESULTS
Thioredoxin-interacting protein was induced during hypoxia in pancreatic cancer cells in a HIF-1alpha-dependent manner. Overexpression of TXNIP in the Panc-1 cells resulted in a higher basal apoptosis and increased sensitivity to cisplatin and oxaliplatin. A negative correlation was observed between TXNIP and thioredoxin 1 expression in human pancreatic cancer tissues.


CONCLUSIONS
Thioredoxin-interacting protein, a putative tumor suppressor gene, is induced in response to hypoxia in a HIF-1alpha-dependent manner in pancreatic cancer cells, resulting in increased apoptosis and increased sensitivity to platinum anticancer therapy. Increased TXNIP may be a mechanism to counterbalance the prosurvival effects of HIF-1alpha.
Baker
Amanda F
AF
College of Medicine, Hematology/Oncology, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA. abaker@azcc.arizona.edu
Koh
Mei Y
MY
Williams
Ryan R
RR
James
Brian
B
Wang
Huamin
H
Tate
Wendy R
WR
Gallegos
Alfred
A
Von Hoff
Daniel D
DD
Han
Haiyong
H
Powis
Garth
G
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D009154:Mutation; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D046888:Tissue Array Analysis; D014162:Transfection; D015854:Up-Regulation
D000970:Antineoplastic Agents; D002352:Carrier Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; C491203:TXN protein, human; C486715:TXNIP protein, human; D000077150:Oxaliplatin; D013879:Thioredoxins; D002945:Cisplatin