Galectin-3 regulates apoptosis and doxorubicin chemoresistance in papillary thyroid cancer cells

doi:10.1016/j.bbrc.2008.12.153

Biochemical and Biophysical Research Communications

Volume 379, Issue 2, 6 February 2009, Pages 626-631

https://doi.org/10.1016/j.bbrc.2008.12.153 Get rights and content

Abstract

A subset of patients with papillary thyroid cancer (PTC) present with aggressive disease that is refractory to conventional treatment. Novel therapies are needed to treat this group of patients. Galectin-3 (Gal-3) is a β-galactoside-binding protein with anti-apoptotic activity. Over 30 studies in the last 3 years have reported that Gal-3 is highly expressed in PTC relative to normal thyrocytes. In this study, we show that Gal-3 silencing with RNA interference stimulates apoptosis, while Gal-3 overexpression protects against both TRAIL- and doxorubicin-induced apoptosis in PTC cells. The anti-apoptotic activity and chemoresistance related to Gal-3 function can be partially reversed through the inhibition of the PI3K-Akt pathway, suggesting that Gal-3 acts, at least in part, on the PI3K-Akt axis. These observations support further evaluation of Gal-3 as a potential therapeutic target in patients with aggressive PTC.

Section snippets

Methods

Materials. Rabbit anti-human phospho-Akt Ser473 antibody was purchased from Cell Signaling Technology (Danver, MA), and goat anti-human Akt1 antibody was purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Rabbit anti-human Gal-3 antibody and TNF-related apoptosis-inducing ligand (TRAIL) were purchased from Sigma–Aldrich (St. Louis, MO) and anti-actin antibody pan Ab-5 was purchased from Neomarker (Fremont, CA). Secondary horseradish peroxidase-conjugated anti-rabbit, -mouse, and -goat

Gal-3 knockdown promotes apoptosis, while Gal-3 overexpression inhibits TRAIL-induced apoptosis in thyroid cancer cells

Transient transfection of Gal-3 RNAi diminished Gal-3 protein expression by 70% and 83% in 8505-C and TPC-1 cells, respectively. Transfection with pCMV6-Gal-3 increased Gal-3 protein expression by 56% and 67% in 8505-C and TPC-1 cells, respectively (Fig. 1A). Gal-3 knockdown induced apoptotic cell death in both 8505-C and TPC-1 cells, with 97% and 69% increases in the apoptotic fraction of cells, respectively (Fig. 1B). Overexpression of Gal-3, following transfection with pCMV6-Gal-3, in 8505-C

Discussion

Our observations show that Gal-3 is an important anti-apoptotic factor in PTC cells and that Gal-3 silencing enhances chemosensitivity to doxorubicin. Gal-3 knockdown by siRNA significantly increased the apoptotic fraction in both 8505-C and TPC-1 cells (Fig. 1). Furthermore, the forced overexpression of Gal-3 inhibited TRAIL- and doxorubicin-induced apoptosis in these cells (Fig. 1, Fig. 2). Similarly, Gal-3 overexpression increased doxorubicin chemoresistance (Fig. 3), an effect that is

Acknowledgments

We thank Dr. Orlo H. Clark (University of California at San Francisco, San Francisco, CA) and Dr. Sareh Parangi (Massachusetts General Hospital, Boston, MA) for kindly providing TPC-1 and 8505-C cells, respectively. We also would like to thank Dr. J. Dirk Iglehart (Dana-Farber Cancer Institute, Boston, MA) for the doxorubicin.

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Galectin-3 regulates apoptosis and doxorubicin chemoresistance in papillary thyroid cancer cells

Abstract

Section snippets

Methods

Gal-3 knockdown promotes apoptosis, while Gal-3 overexpression inhibits TRAIL-induced apoptosis in thyroid cancer cells

Discussion

Acknowledgments

Methods Enzymol.

Biochim. Biophys. Acta

Hum. Pathol.

Mod. Pathol.

Mod. Pathol.

J. Biol. Chem.

Am. J. Pathol.

J. Invest. Dermatol.

Exp. Cell. Res.

J. Biol. Chem.

Neoplasia

Identification of genes differentially expressed in benign versus malignant thyroid tumors

Clin. Cancer Res.

Familial thyroid carcinoma: a diagnostic algorithm

Adv. Anat. Pathol.

Chemotherapy with doxorubicin in progressive medullary and thyroid carcinoma of the follicular epithelium

Horm. Metab. Res.

Identification of the metastasis-associated, galactoside-binding lectin as a chimeric gene product with homology to an IgE-binding protein

Cancer Res.

Galectins as modulators of tumour progression

Nat. Rev. Cancer