Brain Tumor Biology Unit, CIFA, University of Navarra School of Sciences, Pamplona, Spain.
Cytometry A. 2011 Sep;79(9):672-83. doi: 10.1002/cyto.a.21103. Epub 2011 Jul 19.
The Sonic Hedgehog (Hh) pathway has been implicated in the maintenance of stem or progenitor cells in many adult tissues. Importantly, abnormal Hh pathway activation is also associated with initiation of neoplasia, but its role in tumor growth is still unclear. Here, we demonstrate that cyclopamine, a plant-derived alkaloid product used to inhibit the Hh signaling pathway, reduces the Side Population (SP) obtained by Hoechst 33342 (Ho342) dye measurements. In addition, cyclopamine is able to modulate, along with oxysterols and other products, the ABCG2 transporter by increasing Ho342 and mitoxantrone uptake. Therefore, if the SP is solely measured as a Ho342 dye extruding fraction, this may be significantly modulated by the inhibition of ABCG2 transport fraction, independently from the action of cyclopamine on the Hh pathway. Our results indicate that ABCG2 may act in the upstream regulation of the Hh signaling pathway to protect the stemness of the SP compartment, giving support to the cancer stem cell hypothesis and suggesting that ABCG2 is not only critical for increased resistance to anticancer agents.
Sonic Hedgehog（Hh）信号通路被认为在许多成人组织中的干细胞或祖细胞的维持中起作用。重要的是，异常的 Hh 信号通路激活也与肿瘤发生的起始有关，但它在肿瘤生长中的作用仍不清楚。在这里，我们证明了一种植物来源的生物碱产物——环巴胺，用于抑制 Hh 信号通路，减少了 Hoechst 33342（Ho342）染料测量得到的侧群（SP）。此外，环巴胺能够与氧化固醇和其他产物一起调节 ABCG2 转运体，增加 Ho342 和米托蒽醌的摄取。因此，如果 SP 仅作为 Ho342 染料排出部分进行测量，那么这可能会受到 ABCG2 转运部分抑制的显著调节，而与环巴胺对 Hh 途径的作用无关。我们的结果表明，ABCG2 可能在上游调节 Hh 信号通路中起作用，以保护 SP 区室的干性，为癌症干细胞假说提供支持，并表明 ABCG2 不仅对增加抗癌药物的耐药性至关重要。
