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Transient silencing of galectin-3 expression promotes both in vitro and in vivo drug-induced apoptosis of human pancreatic carcinoma cells

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Abstract

Pancreatic cancer demonstrates a strong resistance to anticancer drugs, presumably due to its resistance to drug induced apoptosis. Although gemcitabine (GEM) might be partially effective for treating advanced pancreatic cancer, its efficacy is still less than satisfactory. Galectin-3 (gal-3), a member of the β-galactoside-binding protein family, is a multifunctional protein with roles in tumor cell adhesion, proliferation, differentiation, angiogenesis, metastasis, and apoptosis. We have utilized gal-3 small interfering RNA (siRNA) to probe whether gal-3 regulates anticancer drug-induced apoptosis in pancreatic cancer cells. We found that Gal-3 siRNA augmented GEM- and cisplatin-induced apoptosis in pancreatic cancer cell lines in vitro. Mitochondrial depolarization induction was increased in gal-3-silenced cells after GEM treatment, resulting in activation of caspase-9, but not caspase-8. Akt phosphorylation was significantly downregulated in gal-3- silenced cells in association with apoptosis. Moreover, intratumoral administration of gal-3 siRNA increased the GEM sensitivity of tumor xenografts produced by subcutaneous inoculation of pancreatic cancer cells into nude mice. These results suggest that gal-3 might provide a novel therapeutic target in pancreatic cancer.

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Abbreviations

gal-3:

Galectin-3

GEM:

Gemcitabine

siRNA:

Small interfering RNA

TNF-α:

Tumor necrosis factor-α

PARP:

Poly ADP-ribose polymerase

ERK:

Extracellular-signal-regulated kinases

JNK:

C-Jun N-terminal kinases

PI3K:

Phosphoinositide 3 kinase

PTEN:

Phosphatase and tension homolog deleted on chromosome 10

FITC:

Fluorescein isothiocyanate

PBS:

Phosphate-buffered saline

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

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Acknowledgments

We thank Dr. Tomoharu Fukumori for supplying the plasmid pGEX-Gal-3. We also thank Hayato Yamauchi and Naritaka Tanaka for their technical assistance and advice. This work was supported in part by a grant 3R37-CA46120-21(AR).

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Authors and Affiliations

  1. Department of General Surgical Science (Surgery I), Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Tsutomu Kobayashi, Tatsuo Shimura, Toshiki Yajima, Norio Kubo, Kenichiro Araki, Wataru Wada, Soichi Tsutsumi, Hideki Suzuki & Hiroyuki Kuwano

  2. Department of Tumor and Host Bioscience, Fukushima University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan

    Tatsuo Shimura

  3. Department of Oncolgy, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Avraham Raz

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  1. Tsutomu Kobayashi
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  2. Tatsuo Shimura
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Correspondence to Tsutomu Kobayashi.

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Kobayashi, T., Shimura, T., Yajima, T. et al. Transient silencing of galectin-3 expression promotes both in vitro and in vivo drug-induced apoptosis of human pancreatic carcinoma cells. Clin Exp Metastasis 28, 367–376 (2011). https://doi.org/10.1007/s10585-011-9376-x

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  • DOI: https://doi.org/10.1007/s10585-011-9376-x

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