Nicotine promotes apoptosis resistance of breast cancer cells and enrichment of side population cells with cancer stem cell-like properties via a signaling cascade involving galectin-3, α9 nicotinic acetylcholine receptor and STAT3

Abstract

Nicotine, a main addictive compound in tobacco smoke, has been linked to promotion and progression of lung, head and neck, pancreatic, and breast cancers, but the detailed mechanisms of cancer progression remain elusive. Here, we show that nicotine induces the expression of galectin-3 (an anti-apoptotic β-galactoside-binding lectin) in breast cancer cell line and in primary tumors from breast cancer patients. Nicotine-induced up regulation of galectin-3 is due to an increased expression of α9 isoform of nicotinic acetylcholine receptor (α9nAChR), which activates transcription factor STAT3 that in turn, physically binds to galectin-3 (LGALS3) promoter and induces transcription of galectin-3. Intracellular galectin-3 increased mitochondrial integrity and suppressed chemotherapeutic-induced apoptosis of breast cancer cell. Moreover, nicotine-induced enrichment of side population cells with cancer stem cell-like properties was modulated by galectin-3 expression and could be significantly reduced by transient knock down of LGALS3 and its upstream signaling molecules STAT3 and α9nAChR. Thus, galectin-3 or its upstream signaling molecule STAT3 or α9nAChR could be a potential target to prevent nicotine-induced chemoresistance in breast cancer.

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Abbreviations

α9nAChR:

α9 isoform of nicotinic acetylcholine receptor

LGALS3:

Galectin-3

gal3:

galectin-3

STS:

Staurosporine

SP:

Side population

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Acknowledgments

We are grateful to Dr. Aditi Banerjee for her help on the scratch-wound healing assay. This study was supported by the University of Maryland Start-up fund and in part by the NIH Grants RO3CA133935 and R41CA141970 to H.A; and R01CA105005 and Cigarette Restitution Funds from the University of Maryland Greenebaum Cancer Center to D.V.K.

Conflict of interest

The authors declare that they have no conflict of interest.

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Correspondence to Hafiz Ahmed.

Additional information

Prasun Guha and Gargi Bandyopadhyaya have contributed equally.

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Guha, P., Bandyopadhyaya, G., Polumuri, S.K. et al. Nicotine promotes apoptosis resistance of breast cancer cells and enrichment of side population cells with cancer stem cell-like properties via a signaling cascade involving galectin-3, α9 nicotinic acetylcholine receptor and STAT3. Breast Cancer Res Treat 145, 5–22 (2014). https://doi.org/10.1007/s10549-014-2912-z

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Keywords

  • Nicotine
  • Apoptosis
  • Metastatic cancer
  • Stem cell
  • Galectin-3