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 IC50 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.
Conclusion
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.
aDepartment of Surgery, Brigham and Women's Hospital, Boston, MA
bDepartment of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA
cDepartment of Surgery, University of California at San Francisco, San Francisco, CA
Reprint requests: Daniel T. Ruan, MD, Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
Supported by research grants from the Department of Surgery, Brigham and Women's Hospital, Boston, MA.
Presented at the 30th Annual Meeting of the American Association of Endocrine Surgeons, Madison, Wisconsin, May 2–5, 2009.
ABSTRACT