Schwab Melissa, Multhoff Gabriele
Radiation Immuno-Oncology Group, Center for Translational Cancer Research (TranslaTUM), School of Medicine, Klinikum Rechts der Isar, Technical University of Munich (TUM), Munich, Germany.
Department of Radiation Oncology, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich (TUM), Munich, Germany.
Front Oncol. 2022 Apr 7;12:861266. doi: 10.3389/fonc.2022.861266. eCollection 2022.
As overexpression and membrane localization of stress proteins together with high lactate levels promote radioresistance in tumor cells, we studied the effect of the Hsp90 inhibitor NVP-AUY922 on the cytosolic and membrane expression of heat shock proteins (HSPs) and radiosensitivity in murine melanoma (B16F10) and human colorectal (LS174T) wildtype (WT) and double knockout (LDH) tumor cells. Double knockout for has been found to reduce cytosolic as well as membrane HSP levels, whereas treatment with NVP-AUY922 stimulates the synthesis of Hsp27 and Hsp70, but does not affect membrane Hsp70 expression. Despite NVP-AUY922-inducing elevated levels of cytosolic HSP, radiosensitivity was significantly increased in WT cells and even more pronounced in LDH cells. An impaired lipid metabolism in LDH cells reduces the Hsp70 membrane-anchoring sphingolipid globotriaosylceramide (Gb3) and thereby results in a decreased Hsp70 cell surface density on tumor cells. Our results demonstrate that the membrane Hsp70 density, but not cytosolic HSP levels determines the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in LDH cells.
由于应激蛋白的过表达和膜定位以及高乳酸水平会促进肿瘤细胞的放射抗性，我们研究了热休克蛋白90（Hsp90）抑制剂NVP - AUY922对小鼠黑色素瘤（B16F10）和人结肠直肠癌（LS174T）野生型（WT）及双敲除（LDH）肿瘤细胞中热休克蛋白（HSPs）的胞质和膜表达以及放射敏感性的影响。已发现双敲除会降低胞质以及膜HSP水平，而用NVP - AUY922处理会刺激Hsp27和Hsp70的合成，但不影响膜Hsp70的表达。尽管NVP - AUY922诱导胞质HSP水平升高，但WT细胞的放射敏感性显著增加，在LDH细胞中更为明显。LDH细胞中受损的脂质代谢会减少Hsp70膜锚定鞘脂球三糖神经酰胺（Gb3），从而导致肿瘤细胞膜表面Hsp70密度降低。我们的结果表明，膜Hsp70密度而非胞质HSP水平决定了Hsp90抑制剂NVP - AUY922对LDH细胞的放射增敏作用。
