Saltar al contenido
Merck

Prostate cancer stem-like cells proliferate slowly and resist etoposide-induced cytotoxicity via enhancing DNA damage response.

Experimental cell research (2014-08-26)
Judy Yan, Damu Tang
RESUMEN

Despite the development of chemoresistance as a major concern in prostate cancer therapy, the underlying mechanisms remain elusive. In this report, we demonstrate that DU145-derived prostate cancer stem cells (PCSCs) progress slowly with more cells accumulating in the G1 phase in comparison to DU145 non-PCSCs. Consistent with the important role of the AKT pathway in promoting G1 progression, DU145 PCSCs were less sensitive to growth factor-induced activation of AKT in comparison to non-PCSCs. In response to etoposide (one of the most commonly used chemotherapeutic drugs), DU145 PCSCs survived significantly better than non-PCSCs. In addition to etoposide, PCSCs demonstrated increased resistance to docetaxel, a taxane drug that is commonly used to treat castration-resistant prostate cancer. Etoposide produced elevated levels of γH2AX and triggered a robust G2/M arrest along with a coordinated reduction of the G1 population in PCSCs compared to non-PCSCs, suggesting that elevated γH2AX plays a role in the resistance of PCSCs to etoposide-induced cytotoxicity. We have generated xenograft tumors from DU145 PCSCs and non-PCSCs. Consistent with the knowledge that PCSCs produce xenograft tumors with more advanced features, we were able to demonstrate that PCSC-derived xenograft tumors displayed higher levels of γH2AX and p-CHK1 compared to non-PCSC-produced xenograft tumors. Collectively, our research suggests that the elevation of DNA damage response contributes to PCSC-associated resistance to genotoxic reagents.

MATERIALES
Referencia del producto
Marca
Descripción del producto

Sigma-Aldrich
DAPI, for nucleic acid staining
Sigma-Aldrich
Yoduro de propidio, ≥94.0% (HPLC)
Sigma-Aldrich
Etoposide, synthetic, 95.0-105.0%, powder
Sigma-Aldrich
Hematoxylin
Sigma-Aldrich
Hematoxylin, certified by the Biological Stain Commission
Sigma-Aldrich
Propidium iodide solution
Sigma-Aldrich
Yoduro de propidio, ≥94% (HPLC)
Etoposide, European Pharmacopoeia (EP) Reference Standard
Etoposide for system suitability, European Pharmacopoeia (EP) Reference Standard