Autophagy: a new target for advanced papillary thyroid cancer therapy.
BACKGROUND
Autophagy is a conserved response to stress that facilitates cell survival in some contexts and promotes cell death in others. We sought to characterize autophagy in papillary thyroid cancer (PTC), and to determine the effects of autophagy inhibition on chemosensitivity and radiosensitivity.


METHODS
The human thyroid papillary carcinoma cell lines TPC-1 and 8505-C were treated with doxorubicin or radiation in the presence or absence of the autophagy-specific inhibitor 3-methyladenine (3-MA).


RESULTS
Although light chain 3 (LC3)-II protein levels were undetectable in normal thyroid and PTC specimens at baseline, doxorubicin exposure induced LC3-II expression and the formation of autophagosomes. Both PTC cell lines expressed low levels of LC3-II under standard conditions. Treatment of these cells with doxorubicin strongly induced LC3-II expression and the formation of autophagosomes; however, doxorubicin-mediated induction of LC3-II was abrogated by 3-MA. Moreover, 3-MA significantly increased the doxorubicin IC(50) in both PTC cell lines. Radiation exposure also induced LC3-II expression. Treatment with 3-MA abrogated the radiation-induced increase in LC3-II in both cell lines and reduced radiosensitivity by 49% and 31% in 8505-C and TPC-1 cells, respectively.


CONCLUSIONS
Autophagy inhibition promotes PTC resistance to doxorubicin and radiation. Therefore, autophagy activation may be a useful adjunct treatment for patients with PTC that is refractory to conventional therapy.
Lin
Chi-Iou
CI
Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
Whang
Edward E
EE
Abramson
Michael A
MA
Jiang
Xiaofeng
X
Price
Brendan D
BD
Donner
David B
DB
Moore
Francis D
FD
Ruan
Daniel T
DT
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D002291:Carcinoma, Papillary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*
D000903:Antibiotics, Antineoplastic; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C025946:3-methyladenine; D004317:Doxorubicin; D000225:Adenine