Antimetastatic Action of Pentoxifylline, a Methyl Xanthine Derivative, Through its Effect on PKC Mediated Integrin Transport in B16F10 Melanoma Cells

Aparna Ratheesh, Meenakashi Jain, Rajiv P Gude

Abstract


Background: Integrins are adhesion molecules known to regulate cellular processes like adhesion, migration and proliferation. At the same time role of integrin in progress of cancer metastasis is well established, increased integrin expression is reported to be linked to high metastasis potential of cells. Pentoxifylline a methyl xanthine derivative is a potent antimetastatic agent. Studies on the mechanism of inhibition of lung homing of B16F10 melanoma cells by PTX shows that it can inhibit cell- Extracellular Matrix adhesion, cell surface integrin expression as well as Protein kinase C activity. Previous study from our laboratory have shown PTX treatment can selectively inhibit the cell surface expression of α5 integrin in B16F10 cells without affecting its total cellular protein levels. Numerous studies have documented that differences in surface expression and distribution of integrins affects metastasis. The purpose of present study is to observe the effect of PTX on cellular distribution/ redistribution of integrins and to study the underlying molecular mechanism of PTX action.

Methods: Integrin internalization and transport was observed using immunofluorescence confocal microscopy. PKC activity was determined using MBP4-14 as a substrate. Immunoprecipitation and western blotting was used to show association between PKC and α5 integrin, cell adhesion assay was performed using fibronectin/fibrinogen as substrate.

Results: Immunofluorescence studies showed that PTX treatment caused a redistribution of α5 integrins from the plasma membrane to a perinuclear compartment where it colocalized with Transferrin receptor and Rab-11 GTPase. Rate of integrin internalization and recycling showed that PTX inhibited the recycling of α5 integrins from perinuclear recycling endosomes. PTX is reported to affect kinases; here we showed that PTX inhibited total PKC activity. Association between α5β1 integrin and PKC is studied using Immunoprecipitation which show that PTX affects α5β1 integrin associated PKC activity without affecting the levels of PKC. Studying the effect of delay in integrin recycling on cell functionality showed that it affects spreading of cells on fibronectin/fibrinogen.

Conclusions: Data in the present study shows that PTX interferes with PKC activity bringing about a change in integrin distribution, and there by affecting the functionality of the cell. And this may possibly serve as one of the mechanisms for antimetastatic action of PTX.

 



doi:10.4021/wjon252e


Keywords


Pentoxifylline; Integrin; Internalization; Recycling; Protein kinase C

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