Article

Autophagy: A new target for advanced papillary thyroid cancer therapy

Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
Surgery (Impact Factor: 3.38). 12/2009; 146(6):1208-14. DOI: 10.1016/j.surg.2009.09.019
Source: PubMed

ABSTRACT

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.
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).
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.
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.

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    • "AJ-5 treatment also activated markers of autophagy in both breast cancer cell lines and inhibition of autophagy significantly decreased the level of cell death induced by AJ-5. The induction of autophagic cell death together with apoptosis has also been shown for several other anti-cancer therapies [57] [58] [59] [60] [61] [62] [63]. For example, 5-FU, arsenic trioxide (As2O3) and paclitaxel induce cytotoxicity in many cancer types (colon, acute promyelocytic leukaemia, glioma and ovarian cancer) which is associated with the upregulation of autophagy markers and blocking autophagy reversed the cytotoxic effect of these drugs [38,39,57,64–69]. "

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    • "AJ-5 treatment also activated markers of autophagy in both breast cancer cell lines and inhibition of autophagy significantly decreased the level of cell death induced by AJ-5. The induction of autophagic cell death together with apoptosis has also been shown for several other anti-cancer therapies [57] [58] [59] [60] [61] [62] [63]. For example, 5-FU, arsenic trioxide (As2O3) and paclitaxel induce cytotoxicity in many cancer types (colon, acute promyelocytic leukaemia, glioma and ovarian cancer) which is associated with the upregulation of autophagy markers and blocking autophagy reversed the cytotoxic effect of these drugs [38,39,57,64–69]. "
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