Abstract
Durable tumor cell eradication by chemotherapy is challenged by the development of multidrug-resistance (MDR) and the failure to induce immunogenic cell death. The aim of this work was to investigate whether MDR and immunogenic cell death share a common biochemical pathway eventually amenable to therapeutic intervention. We found that mevalonate pathway activity, Ras and RhoA protein isoprenylation, Ras- and RhoA-downstream signalling pathway activities, Hypoxia Inducible Factor-1alpha activation were significantly higher in MDR+ compared with MDR− human cancer cells, leading to increased P-glycoprotein expression, and protection from doxorubicin-induced cytotoxicity and immunogenic cell death. Zoledronic acid, a potent aminobisphosphonate targeting the mevalonate pathway, interrupted Ras- and RhoA-dependent downstream signalling pathways, abrogated the Hypoxia Inducible Factor-1alpha-driven P-glycoprotein expression, and restored doxorubicin-induced cytotoxicity and immunogenic cell death in MDR+ cells. Immunogenic cell death recovery was documented by the ability of dendritic cells to phagocytise MDR+ cells treated with zoledronic acid plus doxorubicin, and to recruit anti-tumor cytotoxic CD8+ T lymphocytes. These data indicate that MDR+ cells have an hyper-active mevalonate pathway which is targetable with zoledronic acid to antagonize their ability to withstand chemotherapy-induced cytotoxicity and escape immunogenic cell death.
Highlights
The mevalonate (Mev) pathway is a highly conserved metabolic cascade which produces sterols, such as cholesterol, and isoprenoids, such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP)
Intracellular Dox retention, mdr1 mRNA levels, and cholesterol synthesis were measured as markers of Pgp activity, Pgp expression, and Mev pathway activity in HT29, A549, MCF7 cells (MDR2 cells), HT29-dx, A549-dx, MCF7-dx cells, and HepG2 cells, HP06, HMM cells, respectively
CRT translocation was confirmed with a biotinylation assay in both MDR2 and MDR+ cells (Figure S2). These results indicate that the increased Dox retention induced by Zoledronic acid (ZA) treatment is sufficient to induce tumor cell cytotoxicity and to promote immunogenic cell death (ICD) of MDR+ cells
Summary
The mevalonate (Mev) pathway is a highly conserved metabolic cascade which produces sterols, such as cholesterol, and isoprenoids, such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) The latter are necessary for the isoprenylation and activity of small G-proteins such as Ras and Rho which control cell proliferation, cytoskeleton remodelling and angiogenesis [1]. The plasma membranes of MDR+ tumor cells are rich in cholesterol which facilitates the activity of Pglycoprotein (Pgp) [5], an integral membrane transporter extruding chemotherapy drugs such as anthracyclines, taxanes, Vinca alkaloids, epipodophyllotoxins, topotecan, and mitomycin C [4] Another hallmark of MDR+ tumor cells is the increased isoprenylation and activity of G-proteins which are dependent on the rate of the Mev pathway activity [6,7]
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