CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling

Manara, Maria Cristina; Terracciano, Mario; Mancarella, Caterina; Sciandra, Marika; Guerzoni, Clara; Pasello, Michela; Grilli, Andrea; Zini, Nicoletta; Picci, Piero; Colombo, Mario P.; Morrione, Andrea; Scotlandi, Katia

doi:10.18632/oncotarget.13160

Cited by 38 publications

(41 citation statements)

References 53 publications

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“…Although a large number of molecules were shown to induce phenotypes similar to JB-induced vacuolation (69), a specific readout defining macropinocytic vacuole accumulation has not yet been provided. However, the involvement of Ras and Src proteins appears to be a common element in dysregulated macropinocytosis and vacuolation-induced cell death (69)(70)(71)(72) and might represent key molecules for JB-induced vacuolation. However, at present, we do not know whether methuosis is also induced by JB, but we suggest that JB might be a useful tool to examine this novel cell death pathway.…”

Section: Discussionmentioning

confidence: 99%

Jaspine B induces nonapoptotic cell death in gastric cancer cells independently of its inhibition of ceramide synthase

Cingolani

Simbari

Abad

et al. 2017

Journal of Lipid Research

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Sphingolipids (SLs) have been extensively investigated in biomedical research due to their role as bioactive molecules in cells. Here, we describe the effect of a SL analog, jaspine B (JB), a cyclic anhydrophytosphingosine found in marine sponges, on the gastric cancer cell line, HGC-27. JB induced alterations in the sphingolipidome, mainly the accumulation of dihydrosphingosine, sphingosine, and their phosphorylated forms due to inhibition of ceramide synthases. Moreover, JB provoked atypical cell death in HGC-27 cells, characterized by the formation of cytoplasmic vacuoles in a time and dose-dependent manner. Vacuoles appeared to originate from macropinocytosis and triggered cytoplasmic disruption. The pan-caspase inhibitor, z-VAD, did not alter either cytotoxicity or vacuole formation, suggesting that JB activates a caspase-independent cell death mechanism. The autophagy inhibitor, wortmannin, did not decrease JB-stimulated LC3-II accumulation. In addition, cell vacuolation induced by JB was characterized by single-membrane vacuoles, which are different from double-membrane autophagosomes. These findings suggest that JB-induced cell vacuolation is not related to autophagy and it is also independent of its action on SL metabolism.

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Section: Discussionmentioning

confidence: 99%

Jaspine B induces nonapoptotic cell death in gastric cancer cells independently of its inhibition of ceramide synthase

Cingolani

Simbari

Abad

et al. 2017

Journal of Lipid Research

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“…HeLa, SiHa [26,27] lung adenocarcinoma KRAS, integrin avb3, galectin-3 H1792, A549, SKLU1, H1299 subcutaneous patient-derived (PDX) xenograft tumours [28 -30] osteosarcoma ? HOS, 6647 [31,32] ovarian adenocarcinoma ? OVCAR-3, SKOV-3, OV2008 drug delivery is becoming an important field of research in cancer biology and has been the topic of many other excellent reviews [41][42][43][44].…”

Section: Nras?mentioning

confidence: 99%

The pervasiveness of macropinocytosis in oncological malignancies

Commisso

2018

Phil. Trans. R. Soc. B

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In tumour cells, macropinocytosis functions as an amino acid supply route and supports cancer cell survival and proliferation. Initially demonstrated in oncogenic KRAS -driven models of pancreatic cancer, macropinocytosis triggers the internalization of extracellular proteins via discrete endocytic vesicles called macropinosomes. The incoming protein cargo is targeted for lysosome-dependent degradation, causing the intracellular release of amino acids. These protein-derived amino acids support metabolic fitness by contributing to the intracellular amino acid pools, as well as to the biosynthesis of central carbon metabolites. In this way, macropinocytosis represents a novel amino acid supply route that tumour cells use to survive the nutrient-poor conditions of the tumour microenvironment. Macropinocytosis has also emerged as an entry mechanism for a variety of nanomedicines, suggesting that macropinocytosis regulation in the tumour setting can be harnessed for the delivery of anti-cancer therapeutics. A slew of recent studies point to the possibility that macropinocytosis is a pervasive feature of many different tumour types. In this review, we focus on the role of this important uptake mechanism in a variety of cancers and highlight the main molecular drivers of macropinocytosis in these malignancies. This article is part of the Theo Murphy meeting issue ‘Macropinocytosis’.

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“…The vacuoles were generally devoid of cytoplasmic components or organelles, although some contained unidentified membranous inclusions or small quantities of amorphous electron-dense material. Uptake of lucifer yellow provides consolidated evidence that TBM1 induced vacuolization can be mainly defined as macropincytosis which subsequently leads to methuosis ( Manara et al, 2016 ; Cingolani et al, 2017 ).…”

Section: Discussionmentioning

confidence: 92%

Tubeimoside 1 Acts as a Chemotherapeutic Synergist via Stimulating Macropinocytosis

et al. 2018

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Macropinocytosis is a highly conserved endocytic process which characterizes the engulfment of extracellular fluid and its contents into cells via large, heterogeneous vacuoles known as macropinosomes. Tubeimoside-1 (TBM1) is a low toxic triterpenoid saponin extracted from a traditional Chinese herb Bolbostemma paniculatum (Maxim.). TBM1 stimulates a quick accumulation of numerous phase-lucent cytoplasmic vacuoles in multiple colorectal cancer (CRC) cell lines. These vacuoles can be termed as macropinosomes that efficiently engulf lucifer yellow. These vesicles are not overlaps with endocytic organelle tracers, such as ERTracker, LysoTracker and mitoTracker. These vacuoles induced by TBM1 partially incorporate into lysosomes. Transmission electron microscope indicates membrane ruffling to form lamellipodia. Protrusions collapse onto and then fuse back with the plasma membrane to generate these large endocytic vacuoles. Notably, TBM1 efficiently trafficks dextrans into heterotopic xenografts in vivo, thus provide consolidated evidence that the vacuolization can be mainly defined as macropinocytosis. TBM1 downregulates cell viability and increases PI-positive, but not highlighted Hoechst 33342-positive cells. TBM1 induced cell death can be ascribed as methuosis by hyperstimulation of macropinocytosis which can be compromised by amiloride derivative 5-(Nethyl-N-isopropyl). Light chain 3 II is recruited to these vesicles to stimulate macropinocytosis. The cell death and vacuoles can be significantly neutralized by chloroquine, but can not be the inhibited by 3-methyladenine. TBM1 can coordinate with 5-FU to exert toxicity reducing and efficacy enhancing effects in vivo by increasing the uptake of the latter without hepatic injury. In conclusion, TBM1 effectively induces in vitro and in vivo macropinocytosis which can traffick small molecules into CRC cells. It is an attractive drug transporter and can be harnessed as a chemotherapeutic synergist with translational potential.

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CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling

Cited by 38 publications

References 53 publications

Jaspine B induces nonapoptotic cell death in gastric cancer cells independently of its inhibition of ceramide synthase

Jaspine B induces nonapoptotic cell death in gastric cancer cells independently of its inhibition of ceramide synthase

The pervasiveness of macropinocytosis in oncological malignancies

Tubeimoside 1 Acts as a Chemotherapeutic Synergist via Stimulating Macropinocytosis

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