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Down-regulation of ALDH1A3, CD44 or MDR1 sensitizes resistant cancer cells to FAK autophosphorylation inhibitor Y15

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Focal adhesion kinase is an important survival signal in cancer. Recently, we demonstrated that the autophosphorylation inhibitor of FAK, Y15, effectively inhibited cancer cell growth. We detected many cancer cell lines sensitive to Y15 and also detected several cell lines such as colon cancer Lovo-1 and thyroid K1 more resistant to Y15. We sought to determine the main players responsible for the resistance.

Methods

To reveal the signaling pathways responsible for the increased resistance of these cancer cells to the inhibitor of FAK, we performed a microarray gene profile study in both sensitive and resistant cells treated with Y15 inhibitor to compare with the more sensitive cells.

Results

Among unique genes up-regulated by Y15 in Lovo-1 and K1 resistant cells, a stem cell marker—ALDH1A3—was detected to be up-regulated >twofold. The resistant Lovo-1 and thyroid K1 cells overexpressed ALDH1A3 and CD44 versus sensitive cells. Treatment with ALDH1A3 siRNAs or ALDH inhibitor, DEAB sensitized resistant Lovo-1 and K1 cells to Y15 inhibitor, decreased viability and caused G1 cell cycle arrest more effectively than each agent alone. In addition, down-regulation of CD44 that was overexpressed in resistant Lovo-1 cells with CD44 siRNA effectively decreased the viability of cells in combination with Y15. In addition, down-regulation of overexpressed MDR1 with specific inhibitor, PSC-833, also sensitized resistant colon cancer cells to Y15.

Conclusions

This report clearly demonstrates the mechanism of resistance to FAK autophosphorylation inhibitor and the mechanism to overcome it that is important for developing FAK-targeted therapy approaches.

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Abbreviations

FAK:

Focal adhesion kinase

ALDH:

Aldehyde dehydrogenase

MDR1:

Multidrug resistance gene

siRNA:

Small interfering RNA

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Acknowledgments

We would like to thank Dr. Craig Jones and the Flow Cytometry Core Facility for cell cycle analysis (Roswell Park Cancer Institute). We would like to thank the Genomics and Bioinformatics Core Facilities (Roswell Park Cancer Institute) for microarray and bioinformatics analyses. We would like to thank Dr. Liu Biao for help with GEO numbers at NCBI. We would like to thank Animal Core Facility (Roswell Park Cancer Institute) for mice maintaining help. We would like to thank Dr. Carl Morrison, Dr. Lourdes Ylagan Logan and Pathology Core Facility for help with breast cancer TMA staining and scoring. We would like to thank Timothy Marlowe for his suggestions. The study was supported by NIH Grant CA65910 (WGC), NIH Grant # 5 T32 CA 108456-7 (Roswell Park Cancer Institute) and partly by the NCI Cancer Center Support Grant to the Roswell Park Cancer Institute (CA 16056).

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Authors and Affiliations

  1. Department of Surgical Oncology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY, 14263, USA

    Vita Golubovskaya, Shalana O’Brien, Baotran Ho, Melissa Heffler & William G. Cance

  2. Genomics Shared Resource, Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Jeffrey Conroy

  3. Bioinformatics Core, Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Quang Hu, Dan Wang & Song Liu

Authors
  1. Vita Golubovskaya
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  2. Shalana O’Brien
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  3. Baotran Ho
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  4. Melissa Heffler
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  5. Jeffrey Conroy
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  6. Quang Hu
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  7. Dan Wang
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  8. Song Liu
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  9. William G. Cance
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Correspondence to Vita Golubovskaya or William G. Cance.

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Golubovskaya, V., O’Brien, S., Ho, B. et al. Down-regulation of ALDH1A3, CD44 or MDR1 sensitizes resistant cancer cells to FAK autophosphorylation inhibitor Y15. J Cancer Res Clin Oncol 141, 1613–1631 (2015). https://doi.org/10.1007/s00432-015-1924-3

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  • DOI: https://doi.org/10.1007/s00432-015-1924-3

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