Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways

Kim, Seong M.; Roy, Saurabh G.; Chen, Bin; Nguyen, Tiffany M.; McMonigle, Ryan J.; McCracken, Alison N.; Zhang, Yanling; Kofuji, Satoshi; Hou, Jue; Selwan, Elizabeth; Finicle, Brendan T.; Nguyen, Tricia T; Ravi, Archna; Ramirez, Manuel U.; Wiher, Tim; Guenther, Garret; Kono, Mari; Sasaki, Atsuo T.; Weisman, Lois S.; Potma, Eric O.; Tromberg, Bruce J.; Edwards, Robert A.; Hanessian, Stephen; Edinger, Aimee L.

doi:10.1172/jci87148

Cited by 63 publications

(148 citation statements)

References 60 publications

Supporting

Mentioning

137

Contrasting

Order By: Relevance

“…Moreover, Nf2 −/− cells were relatively insensitive to the lysosomal acidification inhibitor hydroxychloroquine (HCQ) or inhibition of PIKfyve localization (FTY720), which is important for the lysosomal processing of both autophagosomes and macropinosomes ( Fig. 4F; Kim et al 2016). Together, these data suggest that, unlike Ras transformed pancreatic cells, Nf2 −/− LDCs and SCs do not depend on or receive benefit from the lysosomal processing of exogenous protein.…”

Section: Altered Macropinosome Processing In Nf2-deficient Cellsmentioning

confidence: 89%

Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface

et al. 2018

View full text Add to dashboard Cite

The architectural and biochemical features of the plasma membrane are governed by its intimate association with the underlying cortical cytoskeleton. The neurofibromatosis type 2 (NF2) tumor suppressor merlin and closely related membrane:cytoskeleton-linking protein ezrin organize the membrane:cytoskeleton interface, a critical cellular compartment that both regulates and is regulated by growth factor receptors. An example of this poorly understood interrelationship is macropinocytosis, an ancient process of nutrient uptake and membrane remodeling that can both be triggered by growth factors and manage receptor availability. We show that merlin deficiency primes the membrane:cytoskeleton interface for epidermal growth factor (EGF)-induced macropinocytosis via a mechanism involving increased cortical ezrin, altered actomyosin, and stabilized cholesterol-rich membranes. These changes profoundly alter EGF receptor (EGFR) trafficking in merlin-deficient cells, favoring increased membrane levels of its heterodimerization partner, ErbB2; clathrin-independent internalization; and recycling. Our work suggests that, unlike Ras transformed cells, merlin-deficient cells do not depend on macropinocytic protein scavenging and instead exploit macropinocytosis for receptor recycling. Finally, we provide evidence that the macropinocytic proficiency of NF2-deficient cells can be used for therapeutic uptake. This work provides new insight into fundamental mechanisms of macropinocytic uptake and processing and suggests new ways to interfere with or exploit macropinocytosis in mutant and other tumors.

show abstract

Section: Altered Macropinosome Processing In Nf2-deficient Cellsmentioning

confidence: 89%

Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The administration of a synthetic sphingolipid (SH-BC-893), which as well blocks other nutrient pathways, shows favorable tumor response [100]. …”

Section: Membrane Modulation Strategies In Cancermentioning

confidence: 99%

Cell membrane modulation as adjuvant in cancer therapy

Zalba

Hagen

2017

Cancer Treatment Reviews

258

240

View full text Add to dashboard Cite

Cancer is a complex disease involving numerous biological processes, which can exist in parallel, can be complementary, or are engaged when needed and as such can replace each other. This redundancy in possibilities cancer cells have, are fundamental to failure of therapy. However, intrinsic features of tumor cells and tumors as a whole provide also opportunities for therapy. Here we discuss the unique and specific makeup and arrangement of cell membranes of tumor cells and how these may help treatment. Interestingly, knowledge on cell membranes and associated structures is present already for decades, while application of membrane modification and manipulation as part of cancer therapy is lagging. Recent developments of scientific tools concerning lipids and lipid metabolism, opened new and previously unknown aspects of tumor cells and indicate possible differences in lipid composition and membrane function of tumor cells compared to healthy cells. This field, coined Lipidomics, demonstrates the importance of lipid components in cell membrane in several illnesses. Important alterations in cancer, and specially in resistant cancer cells compared to normal cells, opened the door to new therapeutic strategies. Moreover, the ability to modulate membrane components and/or properties has become a reality. Here, developments in cancer-related Lipidomics and strategies to interfere specifically with cancer cell membranes and how these affect cancer treatment are discussed. We hypothesize that combination of lipid or membrane targeted strategies with available care to improve chemotherapy, radiotherapy and immunotherapy will bring the much needed change in treatment in the years to come.

show abstract

“…FTY720 is a pro-drug, and FTY720 phosphate produced intracellularly is responsible for the therapeutic, immunosuppressive actions via stimulation of sphingosine-1phosphate (S1P) receptors (Brinkmann et al, 2010). Unphosphorylated FTY720, in contrast, limits tumor cell growth and survival in vitro and in vivo by activating PP2A and disrupting endocytic trafficking (Kim et al, 2016;Romero Rosales et al, 2011). Unlike FTY720, the conformationally constrained FTY720 analog SH-BC-893 (893) does not activate S1P receptors, even in its phosphorylated form (Chen et al, 2016;Kim et al, 2016;Perryman et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Unphosphorylated FTY720, in contrast, limits tumor cell growth and survival in vitro and in vivo by activating PP2A and disrupting endocytic trafficking (Kim et al, 2016;Romero Rosales et al, 2011). Unlike FTY720, the conformationally constrained FTY720 analog SH-BC-893 (893) does not activate S1P receptors, even in its phosphorylated form (Chen et al, 2016;Kim et al, 2016;Perryman et al, 2016). However, FTY720 and 893 produce identical disruptions in intracellular trafficking, and their IC50 values are closely matched, suggesting that effects on trafficking, not S1P receptors, are responsible for the anti-cancer activity of FTY720 (Kim et al, 2016;Romero Rosales et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Sphingolipids inhibit endosomal recycling of nutrient transporters by inactivating ARF6

Finicle

Ramirez

Liu

et al. 2018

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

Endogenous sphingolipids (ceramide) and related synthetic molecules (FTY720, SH-BC-893) reduce nutrient access by decreasing cell surface expression of a subset of nutrient transporter proteins. Here, we report that these sphingolipids disrupt endocytic recycling by inactivating the small GTPase ARF6. Consistent with reported roles for ARF6 in maintaining the tubular recycling endosome, MICAL-L1-positive tubules were lost from sphingolipid-treated cells. We propose that ARF6 inactivation may occur downstream of PP2A activation since: (1) sphingolipids that fail to activate PP2A did not reduce ARF6-GTP levels; (2) a structurally unrelated PP2A activator disrupted tubular recycling endosome morphology and transporter localization; and (3) overexpression of a phosphomimetic mutant of the ARF6 GEF GRP1 prevented nutrient transporter loss. ARF6 inhibition alone was not toxic; however, the ARF6 inhibitors SecinH3 and NAV2729 dramatically enhanced the killing of cancer cells by SH-BC-893 without increasing toxicity to peripheral blood mononuclear cells, suggesting that ARF6 inactivation contributes to the anti-neoplastic actions of sphingolipids. Taken together, these studies provide mechanistic insight into how ceramide and sphingolipid-like molecules limit nutrient access and suppress tumor cell growth and survival.

show abstract

Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways

Cited by 63 publications

References 60 publications

Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface

Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface

Cell membrane modulation as adjuvant in cancer therapy

Sphingolipids inhibit endosomal recycling of nutrient transporters by inactivating ARF6

Contact Info

Product

Resources

About