Thyroid cancer resistance to chemotherapeutic drugs via autocrine production of interleukin-4 and interleukin-10.
We investigated the mechanisms responsible for the widespread refractoriness to chemotherapeutic drugs observed in thyroid cancers. We show that malignant epithelial cells from papillary, follicular, and anaplastic thyroid carcinomas express high levels of Bcl-2 and Bcl-xL. Exogenous expression of either Bcl-2 or Bcl-xL in normal thyrocytes was sufficient to prevent chemotherapeutic drug-induced cytotoxicity. All of the histological thyroid cancer variants examined produced interleukin-4 (IL-4) and interleukin-10 (IL-10), which increased Bcl-2 and Bcl-xL levels and protected thyroid cells from chemotherapeutic agents. Exposure to neutralizing antibodies against IL-4 and IL-10 resulted in down-modulation of Bcl-2 and Bcl-xL, death of a considerable percentage of thyroid cancer cells, and sensitization of the residual tumor population to cytotoxic drug-induced apoptosis. In conclusion, autocrine production of IL-4 and IL-10 promotes thyroid tumor cell progression and resistance to chemotherapy through the up-regulation of antiapoptotic proteins. Thus, IL-4 and IL-10 may represent new therapeutic targets for the treatment of thyroid cancer.
Stassi
Giorgio
G
Department of Surgical and Oncological Sciences, University of Palermo, 90127 Palermo, Italy. gstassi@tiscali.it
Todaro
Matilde
M
Zerilli
Monica
M
Ricci-Vitiani
Lucia
L
Di Liberto
Diana
D
Patti
Mariella
M
Florena
Adamaria
A
Di Gaudio
Francesca
F
Di Gesù
Giuseppe
G
De Maria
Ruggero
R
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000502:physiology*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000502:physiology*; D008875:Middle Aged; D017239:Paclitaxel / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000494:pharmacology; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D016753:Interleukin-10; D015847:Interleukin-4; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin