Silencing of Taxol-Sensitizer Genes in Cancer Cells: Lack of Sensitization Effects.

Shang-Lang Huang,Chuck Chao

doi:10.3390/cancers7020824

Abstract

A previous genome-wide screening analysis identified a panel of genes that sensitize the human non-small-cell lung carcinoma cell line NCI-H1155 to taxol. However, whether the identified genes sensitize other cancer cells to taxol has not been examined. Here, we silenced the taxol-sensitizer genes identified (acrbp, atp6v0d2, fgd4, hs6st2, psma6, and tubgcp2) in nine other cancer cell types (including lung, cervical, ovarian, and hepatocellular carcinoma cell lines) that showed reduced cell viability in the presence of a sub-lethal concentration of taxol. Surprisingly, none of the genes studied increased sensitivity to taxol in the tested panel of cell lines. As observed in H1155 cells, SKOV3 cells displayed induction of five of the six genes studied in response to a cell killing dose of taxol. The other cell types were much less responsive to taxol. Notably, four of the five inducible taxol-sensitizer genes tested (acrbp, atp6v0d2, psma6, and tubgcp2) were upregulated in a taxol-resistant ovarian cancer cell line. These results indicate that the previously identified taxol-sensitizer loci are not conserved genetic targets involved in inhibiting cell proliferation in response to taxol. Our findings also suggest that regulation of taxol-sensitizer genes by taxol may be critical for acquired cell resistance to the drug.

Highlights

Paclitaxel and taxanes are microtubule-stabilizing agents that act primarily by interfering with spindle microtubules, causing cell cycle arrest and apoptosis
Considering that taxanes are important chemotherapeutic agents for the treatment of various cancers, we examined the role of representative taxol-sensitizer genes in ten types of cancer cell lines, including four non-small-cell lung carcinomas (NSCLCs): H1155, H1299, H520, and H661
To assess whether the modulatory role of the taxol-sensitizer genes in other cancer cells, we examined the response of nine other types of cancer cell lines, including lung (H1299, H520, H661), liver (Huh7, Hep3B, HepG2), cervical (HeLa), neuroblastoma (HOB1) and ovarian cancer cells (SKOV3)

Summary

Introduction

Paclitaxel (taxol) and taxanes are microtubule-stabilizing agents that act primarily by interfering with spindle microtubules, causing cell cycle arrest and apoptosis. These drugs are used for the treatment of non-small-cell lung cancer (NSCLC) and ovarian cancer, among others. Their therapeutic usefulness is limited by the phenomenon of acquired chemoresistance [1,2]. Drug resistance is associated with several membrane transporters of the ATP-binding cassette (ABC) and solute carrier (SLC) families. Altered expression of microtubule-associated proteins (MAPs) (such as MAP4, stathmin, and tau) may be useful to identify cancer patients who may show recurrence and those most likely to benefit from taxol treatment [2]. Other biomarkers of taxol chemoresistance include specific checkpoint proteins including BRCA1 and the spindle assembly checkpoint proteins MAD2, BUBR1, synuclein-gamma, and aurora A

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