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Published on: February 20, 2017
Proteomics of cancer cell lines resistant to microtubule-stabilizing agents
Jakob Albrethsen1, Ruth H Angeletti, Susan Band Horwitz
1Corresponding Author: Chia-Ping Huang Yang, Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. chia-ping.h.yang@einstein.yu.edu.
Abstract:
Despite the clinical success of microtubule-interacting agents (MIA), a significant challenge for oncologists is the inability to predict the response of individual patients with cancer to these drugs. In the present study, six cell lines were compared by 2D DIGE proteomics to investigate cellular resistance to the class of MIAs known as microtubule-stabilizing agents (MSA). The human lung cancer cell line A549 was compared with two drug-resistant daughter cell lines, a taxol-resistant cell line (AT12) and an epothilone B (EpoB)-resistant cell line (EpoB40). The ovarian cancer cell line Hey was compared with two drug-resistant daughter cell lines, an EpoB-resistant cell line (EpoB8) and an ixabepilone-resistant cell line (Ixab80). All 2D DIGE results were validated by Western blot analyses. A variety of cytoskeletal and cytoskeleton-associated proteins were differentially expressed in drug-resistant cells. Differential abundance of 14-3-3σ, galectin-1 and phosphorylation of stathmin are worthy of further studies as candidate predictive biomarkers for MSAs. This is especially true for galectin-1, a β-galactose-binding lectin that mediates tumor invasion and metastasis. Galectin-1 was greatly increased in EpoB- and ixabepilone-resistant cells and its suppression caused an increase in drug sensitivity in both drug-sensitive and -resistant Hey cells. Furthermore, the growth medium from resistant Hey cells contained higher levels of galectin-1, suggesting that galectin-1 could play a role in resistance to MSAs.
Insights
Predicting patient response to microtubule-stabilizing agents (MSAs) is challenging. This study identified galectin-1 as a potential biomarker for MSA resistance in cancer cells, showing its suppression increases drug sensitivity.
Area of Science:
- Oncology
- Proteomics
- Molecular Biology
Background:
- Microtubule-interacting agents (MIAs) are clinically successful cancer drugs.
- Predicting individual patient response to MIAs remains a significant challenge for oncologists.
Purpose of the Study:
- To investigate cellular resistance mechanisms to microtubule-stabilizing agents (MSAs) using proteomics.
- To identify potential predictive biomarkers for MSA response.
Main Methods:
- Comparative proteomics using 2D DIGE on six cell lines, including drug-sensitive and drug-resistant cancer cell lines (lung and ovarian).
- Validation of proteomic findings using Western blot analyses.
- Investigated the role of galectin-1 in drug resistance and sensitivity.
Main Results:
- Differential expression of cytoskeletal and associated proteins was observed in drug-resistant cells.
- Galectin-1 was significantly increased in epothilone B (EpoB)- and ixabepilone-resistant cells.
- Suppression of galectin-1 enhanced drug sensitivity in both sensitive and resistant ovarian cancer cells, with elevated galectin-1 found in the medium of resistant cells.
Conclusions:
- Galectin-1 is a promising candidate predictive biomarker for microtubule-stabilizing agent (MSA) resistance.
- Galectin-1 may play a direct role in mediating resistance to MSAs.
- Further studies on galectin-1, 14-3-3σ, and stathmin phosphorylation are warranted for biomarker development.
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