MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells.
Sarmistha TalukdarAnjan K PradhanPraveen BhoopathiXue-Ning ShenLaura A AugustJolene J WindleDevanand SarkarFrank B FurnariWebster K CaveneeSwadesh K DasLuni EmdadPaul B FisherPublished in: Proceedings of the National Academy of Sciences of the United States of America (2018)
Glioma stem cells (GSCs) comprise a small subpopulation of glioblastoma multiforme cells that contribute to therapy resistance, poor prognosis, and tumor recurrence. Protective autophagy promotes resistance of GSCs to anoikis, a form of programmed cell death occurring when anchorage-dependent cells detach from the extracellular matrix. In nonadherent conditions, GSCs display protective autophagy and anoikis-resistance, which correlates with expression of melanoma differentiation associated gene-9/Syntenin (MDA-9) (syndecan binding protein; SDCBP). When MDA-9 is suppressed, GSCs undergo autophagic death supporting the hypothesis that MDA-9 regulates protective autophagy in GSCs under anoikis conditions. MDA-9 maintains protective autophagy through phosphorylation of BCL2 and by suppressing high levels of autophagy through EGFR signaling. MDA-9 promotes these changes by modifying FAK and PKC signaling. Gain-of-function and loss-of-function genetic approaches demonstrate that MDA-9 regulates pEGFR and pBCL2 expression through FAK and pPKC. EGFR signaling inhibits autophagy markers (ATG5, Lamp1, LC3B), helping to maintain protective autophagy, and along with pBCL2 maintain survival of GSCs. In the absence of MDA-9, this protective mechanism is deregulated; EGFR no longer maintains protective autophagy, leading to highly elevated and sustained levels of autophagy and consequently decreased cell survival. In addition, pBCL2 is down-regulated in the absence of MDA-9, leading to cell death in GSCs under conditions of anoikis. Our studies confirm a functional link between MDA-9 expression and protective autophagy in GSCs and show that inhibition of MDA-9 reverses protective autophagy and induces anoikis and cell death in GSCs.
Keyphrases
- cell death
- cell cycle arrest
- poor prognosis
- endoplasmic reticulum stress
- breast cancer cells
- stem cells
- signaling pathway
- oxidative stress
- small cell lung cancer
- induced apoptosis
- binding protein
- extracellular matrix
- pi k akt
- gene expression
- epidermal growth factor receptor
- transcription factor
- genome wide
- mesenchymal stem cells
- copy number
- bone marrow
- dna methylation
- tandem mass spectrometry