Cancer stem cells: The potential role of autophagy, proteolysis, and cathepsins in glioblastoma stem cells

Bischof, Joachim; Westhoff, Mike‐Andrew; Wagner, Johanna; Halatsch, Marc‐Eric; Trentmann, Stephanie; Knippschild, Uwe; Wirtz, Christian Rainer; Burster, Timo

doi:10.1177/1010428317692227

Cited by 39 publications

(32 citation statements)

References 171 publications

(205 reference statements)

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“…The stem cell subpopulation in GBM has been proposed to be a central driver of tumor initiation, progression, recurrence and therapeutic resistance (30). To assess the therapeutic effect of CK against cancer stem cell-like phenotypes of GBM cells, spheroid cultures for the expansion of cancer stem cell populations from U87MG and U373MG cells was examined.…”

Section: Resultsmentioning

confidence: 99%

The ginsenoside metabolite compound K inhibits growth, migration and stemness of glioblastoma cells

Lee

Kwon

Jang

et al. 2017

International Journal of Oncology

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Glioblastoma (GBM) is the most aggressive and malignant form of primary brain cancer. Despite recent advances in cancer treatment, it remains a substantially incurable disease. Accordingly, more effective GBM therapeutic options are urgently required. In the present study, we investigated the anticancer effect of a ginsenoside metabolite, compound K (CK), against GBM cells. CK significantly inhibited not only growth, but also metastatic ability of U87MG and U373MG cells. CK arrested cell cycle progression at the G0/G1 phase with a decrease in the expression levels of cyclin D1 and cyclin D3 in both cell types. CK also induced apoptosis in GBM cells through nuclear condensation, an increase in ROS generation, mitochondrial membrane potential depolarization, and activation of caspase-3, caspase-9 and poly(ADP-ribose) polymerase (PARP). Furthermore, CK inhibited phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, contributing to the antiproliferative and apoptotic effects. Moreover, CK suppressed the self-renewal capacity as well as the invasiveness of U87MG and U373MG GBM stem-like cells (GSCs) by inducing a reduction in the expression of GSC markers, such as CD133, Nanog, Oct4 and Sox2. Taken together, our findings suggest that CK may potentially be useful for GBM treatment.

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Section: Resultsmentioning

confidence: 99%

The ginsenoside metabolite compound K inhibits growth, migration and stemness of glioblastoma cells

Lee

Kwon

Jang

et al. 2017

International Journal of Oncology

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“…Autophagy is a (patho-)physiological process occurring in both healthy and malignant cells and can function as either a tumorsuppressing or tumor-promoting factor (1,(9)(10)(11). Autophagy can prevent healthy cells from developing into cancer cells and can promote death in tumor cells.…”

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confidence: 99%

MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells

Talukdar

Pradhan

Bhoopathi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

100

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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.

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“…In cancer cells, however, autophagy plays a variety of tumour-promoting roles, including supporting cellular metabolism to promote cancer cell growth and survival and contributing to therapy resistance. Autophagy can also supports metastasis by protecting detached cells from anoikis, a form of programmed cell death [96,97,98,99,100]. …”

Section: Other Roles Of Nf-κb In Glioblastomamentioning

confidence: 99%

“…The remarkable resistance of GBM to chemo- and radiotherapy is also thought to result in part from the contribution of autophagy to the adaptation capabilities of this cancer [99,100,101]. On the basis of these considerations, the goal of inhibiting mechanisms of autophagy is emerging as an attractive therapeutic approach in GBM.…”

Section: Other Roles Of Nf-κb In Glioblastomamentioning

confidence: 99%

NF-κB Signalling in Glioblastoma

Soubannier

Stifani

2017

Biomedicines

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Nuclear factor-κB (NF-κB) is a transcription factor regulating a wide array of genes mediating numerous cellular processes such as proliferation, differentiation, motility and survival, to name a few. Aberrant activation of NF-κB is a frequent event in numerous cancers, including glioblastoma, the most common and lethal form of brain tumours of glial cell origin (collectively termed gliomas). Glioblastoma is characterized by high cellular heterogeneity, resistance to therapy and almost inevitable recurrence after surgery and treatment. NF-κB is aberrantly activated in response to a variety of stimuli in glioblastoma, where its activity has been implicated in processes ranging from maintenance of cancer stem-like cells, stimulation of cancer cell invasion, promotion of mesenchymal identity, and resistance to radiotherapy. This review examines the mechanisms of NF-κB activation in glioblastoma, the involvement of NF-κB in several mechanisms underlying glioblastoma propagation, and discusses some of the important questions of future research into the roles of NF-κB in glioblastoma.

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Cancer stem cells: The potential role of autophagy, proteolysis, and cathepsins in glioblastoma stem cells

Cited by 39 publications

References 171 publications

The ginsenoside metabolite compound K inhibits growth, migration and stemness of glioblastoma cells

The ginsenoside metabolite compound K inhibits growth, migration and stemness of glioblastoma cells

MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells

NF-κB Signalling in Glioblastoma

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