Abstract
Macropinocytosis is a clathrin-independent endocytosis of extracellular fluid that may contribute to cancer aggressiveness through nutrient supply, recycling of plasma membrane and receptors, and exosome internalization. Macropinocytosis may be notably triggered by epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR), two well-known markers for glioblastoma aggressiveness. Therefore, we studied whether the expression of key actors of macropinocytosis is modified in human glioma datasets. Strong deregulation has been evidenced at the mRNA level according to the grade of the tumor, and 38 macropinocytosis-related gene signatures allowed discrimination of the glioblastoma (GBM) samples. Honokiol-induced vacuolization was then compared to vacquinol-1 and MOMIPP, two known macropinocytosis inducers. Despite high phase-contrast morphological similarities, honokiol-induced vacuoles appeared to originate from both endocytosis and ER. Also, acridine orange staining suggested differences in the macropinosomes’ fate: their fusion with lysosomes appeared very limited in 3-(5-methoxy -2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (MOMIPP)-treated cells. Nevertheless, each of the compounds markedly increased temozolomide uptake by glioma cells, as evidenced by LC-MS. In conclusion, the observed deregulation of macropinocytosis in GBM makes them prone to respond to various compounds affecting their formation and/or intracellular fate. Considering that sustained macropinocytosis may also trigger cell death of both sensitive and resistant GBM cells, we propose to envisage macropinocytosis inducers in combination approaches to obtain dual benefits: increased drug uptake and additive/synergistic effects.
Highlights
Glioblastoma (GBM) remains associated with a dismal prognosis, partly due to a high level of resistance to proapoptotic stimuli and a propensity for cell migration and invasion of normal brainCancers 2019, 11, 411; doi:10.3390/cancers11030411 www.mdpi.com/journal/cancersCancers 2019, 11, 411 tissue [1,2]
To evaluate whether macropinocytosis is deregulated in gliomas, we made use of mRNA
Consistent with existing literature, we found epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) to be upregulated in gliomas [19,20,48]
Summary
Glioblastoma (GBM) remains associated with a dismal prognosis, partly due to a high level of resistance to proapoptotic stimuli and a propensity for cell migration and invasion of normal brainCancers 2019, 11, 411; doi:10.3390/cancers11030411 www.mdpi.com/journal/cancersCancers 2019, 11, 411 tissue [1,2]. The majority of chemotherapeutic drugs operate by triggering caspase-dependent apoptotic cell death, 17 cell death types have been described to date [3,4,5], including autophagy. The latter is a programmed pathway that can either promote or hinder tumor development. It is triggered by several anti-tumor agents, including temozolomide (TMZ), in cancer cells lacking essential apoptotic modulators, such as GBM [6]. Autophagy remains the best way to combat GBM, since it is induced by the standard-of-care drug
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