Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer

Thiruvengadam Arumugam, Vijaya Ramachandran, Keith F. Fournier, Huamin Wang, Lauren Marquis, James L. Abbruzzese, Gary E. Gallick, Craig D. Logsdon, David McConkey, Woonyoung Choi

Research output: Contribution to journalArticle

Abstract

A better understanding of drug resistance mechanisms is required to improve outcomes in patients with pancreatic cancer. Here, we characterized patterns of sensitivity and resistance to three conventional chemotherapeutic agents with divergent mechanisms of action [gemcitabine, 5-fluorouracil (5-FU), and cisplatin] in pancreatic cancer cells. Four (L3.6pl, BxPC-3, CFPAC-1, and SU86.86) were sensitive and five (PANC-1, Hs766T, AsPC-1, MIAPaCa-2, and MPanc96) were resistant to all three agents based on GI50 (50% growth inhibition). Gene expression profiling and unsupervised hierarchical clustering revealed that the sensitive and resistant cells formed two distinct groups and differed in expression of specific genes, including several features of "epithelial to mesenchymal transition" (EMT). Interestingly, an inverse correlation between E-cadherin and its transcriptional suppressor, Zeb-1, was observed in the gene expression data and was confirmed by real-time PCR. Independent validation experiment using five new pancreatic cancer cell lines confirmed that an inverse correlation between E-cadherin and Zeb-1 correlated closely with resistance to gemcitabine, 5-FU, and cisplatin. Silencing Zeb-1 in the mesenchymal lines not only increased the expression of Ecadherin but also other epithelial markers, such as EVA1 and MAL2, and restored drug sensitivity. Importantly, immunohistochemical analysis of E-cadherin and Zeb-1 in primary tumors confirmed that expression of the two proteins was mutually exclusive (P = 0.012). Therefore, our results suggest that Zeb-1 and other regulators of EMT may maintain drug resistance in human pancreatic cancer cells, and therapeutic strategies to inhibit Zeb-1 and reverse EMT should be evaluated.

Original languageEnglish (US)
Pages (from-to)5820-5828
Number of pages9
JournalCancer Research
Volume69
Issue number14
DOIs
StatePublished - Jul 15 2009
Externally publishedYes

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Epithelial-Mesenchymal Transition
Cadherins
Pancreatic Neoplasms
Drug Resistance
gemcitabine
Fluorouracil
Cisplatin
Gene Expression
Gene Expression Profiling
Cluster Analysis
Real-Time Polymerase Chain Reaction
Cell Line
Growth
Pharmaceutical Preparations
Neoplasms
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Arumugam, T., Ramachandran, V., Fournier, K. F., Wang, H., Marquis, L., Abbruzzese, J. L., ... Choi, W. (2009). Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Research, 69(14), 5820-5828. https://doi.org/10.1158/0008-5472.CAN-08-2819

Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. / Arumugam, Thiruvengadam; Ramachandran, Vijaya; Fournier, Keith F.; Wang, Huamin; Marquis, Lauren; Abbruzzese, James L.; Gallick, Gary E.; Logsdon, Craig D.; McConkey, David; Choi, Woonyoung.

In: Cancer Research, Vol. 69, No. 14, 15.07.2009, p. 5820-5828.

Research output: Contribution to journalArticle

Arumugam, T, Ramachandran, V, Fournier, KF, Wang, H, Marquis, L, Abbruzzese, JL, Gallick, GE, Logsdon, CD, McConkey, D & Choi, W 2009, 'Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer', Cancer Research, vol. 69, no. 14, pp. 5820-5828. https://doi.org/10.1158/0008-5472.CAN-08-2819
Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Research. 2009 Jul 15;69(14):5820-5828. https://doi.org/10.1158/0008-5472.CAN-08-2819
Arumugam, Thiruvengadam ; Ramachandran, Vijaya ; Fournier, Keith F. ; Wang, Huamin ; Marquis, Lauren ; Abbruzzese, James L. ; Gallick, Gary E. ; Logsdon, Craig D. ; McConkey, David ; Choi, Woonyoung. / Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. In: Cancer Research. 2009 ; Vol. 69, No. 14. pp. 5820-5828.
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