The expression of translocator protein in human thyroid cancer and its role in the response of thyroid cancer cells to oxidative stress.
The translocator protein (TSPO), formerly known as a peripheral benzodiazepine receptor, exerts pro-apoptotic function via regulation of mitochondrial membrane potential. We examined TSPO expression in human thyroid tumors (25 follicular adenomas (FA), 15 follicular cancers (FC), and 70 papillary cancers (PC)). The role of TSPO in the regulation of cell growth, migration, and apoptosis was examined in thyroid cancer cell lines after TSPO knockdown with siRNA and after treatment with TSPO antagonist (PK11195). Compared with normal thyroid, the level of TSPO expression was increased in FA, FC, and PC in 24, 26.6, and 55.7% of cases respectively. Thyroid cancer cell lines demonstrated variable levels of TSPO expression, without specific association with thyroid oncogene mutations. Treatment with inhibitors of PI3K/AKT or MEK/ERK signaling was not associated with changes in TSPO expression. Treatment with histone deacetylase inhibitor (valproic acid) increased TSPO expression in TSPO-deficient cell lines (FTC236 cells). TSPO gene silencing or treatment with PK11195 did not affect thyroid cancer cell growth and migration but prevented depolarization of mitochondrial membranes induced by oxidative stress. Induction of TSPO expression by valproic acid was associated with increased sensitivity of FTC236 to oxidative stress-inducible apoptosis. Overall, we showed that TSPO expression is frequently increased in PC. In vitro data suggested the role of epigenetic mechanism(s) in the regulation of TSPO in thyroid cells. Implication of TSPO in the thyroid cancer cell response to oxidative stress suggested its potential role in the regulation of thyroid cancer cell response to treatment with radioiodine and warrants further investigation.
Division of Endocrinology, Department of Medicine, Washington Hospital Center, Washington, District of Columbia 20010-2910, USA.
Joanna
J
Klubo-Gwiezdzinska
Kirk
K
Jensen
Andrew
A
Bauer
Aneeta
A
Patel
John
J
Costello
Kenneth D
KD
Burman
Leonard
L
Wartofsky
Matthew J
MJ
Hardwick
Vasyl V
VV
Vasko
D018263:Adenocarcinoma, Follicular; D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D018079:Receptors, GABA / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D007546:Isoquinolines; D018079:Receptors, GABA; C499229:TSPO protein, human; D006861:Hydrogen Peroxide; C037850:PK 11195