Autophagy and lysosomal related protein expression patterns in human glioblastoma

Abstract

Glioblastoma cells are resistant to apoptotic stimuli with autophagic death prevailing under cytotoxic stress. Autophagy interfering agents may represent a new strategy to test in combination with chemo-radiation. We investigated the patterns of expression of autophagy related proteins (LC3A, LC3B, p62, Beclin 1, ULK1 and ULK2) in a series of patients treated with post-operative radiotherapy. Experiments with glioblastoma cell lines (T98 and U87) were also performed to assess autophagic response under conditions simulating the adverse intratumoral environment. Glioblastomas showed cytoplasmic overexpression of autophagic proteins in a varying extent, so that cases could be grouped into low and high expression groups. 10/23, 5/23, 13/23, 5/23, 8/23 and 9/23 cases examined showed extensive expression of LC3A, LC3B, Beclin 1, Ulk 1, Ulk 2 and p62, respectively. Lysosomal markers Cathepsin D and LAMP2a, as well as the lyososomal biogenesis transcription factor TFEB were frequently overexpressed in glioblastomas (10/23, 11/23, and 10/23 cases, respectively). TFEB was directly linked with PTEN, Cathepsin D, HIF1α, LC3B, Beclin 1 and p62 expression. PTEN was also significantly related with LC3B but not LC3A expression, in both immunohistochemistry and gene expression analysis. Confocal microscopy in T98 and U87 cell lines showed distinct identity of LC3A and LC3B autophagosomes. The previously reported stone-like structure (SLS) pattern of LC3 expression was related with prognosis. SLS were inducible in glioblastoma cell lines under exposure to acidic conditions and 2DG mediated glucose antagonism. The present study provides the basis for autophagic characterization of human glioblastoma for further translational studies and targeted therapy trials.

LAMP‐1 gene is overexpressed in high grade glioma

“…LAMP‐1 and LAMP‐2 display differential expression in a variety of cell processes and clinical conditions but their entire biological function is still enigmatic. Their involvement (basically LAMP‐1) in cancer is widely discussed in many aspects especially regarding lysosomal exocytosis as a mediator of cancer progression . Enhanced LAMP‐2A in breast tumors is believed to promote cancer cell survival via chaperone‐mediated autophagy .…”

Development of a novel protein identification approach to define mitochondrial proteomic signatures in glioblastoma oncogenesis: T98G vs U87MG cell lines model

“…In U87MG cells there are more interactions between these proteins, suggesting a specificity of these interactions on advanced cancer. This landscape resembles autophagy, a central process in advanced states of cancer, which enable cancer cell surveillance because of the recycling of metabolites and nutrients [46,47]. In addition, there are proteins for amino-acids and purines metabolism making possible the phagosomes formation [48].…”

Inhibition of TFEB oligomerization by co‐treatment of melatonin with vorinostat promotes the therapeutic sensitivity in glioblastoma and glioma stem cells

“…Moreover, increased expression of TFEB was associated with poor prognosis in patients with NSCLC. These findings suggested that TFEB may also be overexpressed and oligomerized in GBMs …”

“…These findings suggested that TFEB may also be overexpressed and oligomerized in GBMs. [32][33][34] As with most cancers, the prevention of recurrence is important in the treatment of GBMs. GSCs, which possess some of the properties of tumor cells, were recently shown to be important for GBM recurrence.…”