Acid ceramidase confers radioresistance to glioblastoma cells

Abstract

Glioblastoma multiforme (GBM) is the most common primary, intracranial malignancy of the central nervous system. The standard treatment protocol, which involves surgical resection, and concurrent radiation with adjuvant temozolomide (TMZ), still imparts a grim prognosis. Ultimately, all GBMs exhibit recurrence or progression, developing resistance to standard treatment. This study demonstrates that GBMs acquire resistance to radiation via upregulation of acid ceramidase (ASAH1) and sphingosine-1-phosphate (Sph-1P). Moreover, inhibition of ASAH1 and Sph-1P, either with humanized monoclonal antibodies, small molecule drugs (i.e. carmofur), or a combination of both, led to suppression of GBM cell growth. These results suggest that ASAH1 and Sph-1P may be excellent targets for the treatment of new GBMs and recurrent GBMs, especially since the latter overexpresses ASAH1.

Glioblastoma: Pathogenesis and Current Status of Chemotherapy and Other Novel Treatments

“…Ceramides promote senescence and cell death [37]. On the contrary, sphingosine-1-phosphate (S1P), the immediate product due to metabolism, fosters cell survival and proliferation [38]. Histologically confirmed glioma cells have shown a change from ceramides to S1P, leading to higher S1P concentrations than ceramide.…”

“…Histologically confirmed glioma cells have shown a change from ceramides to S1P, leading to higher S1P concentrations than ceramide. With lower amounts of ceramides, apoptosis occurs less, which allows the glioma cells to spread more freely [38]. In addition, modification of ASAH1 in glioblastoma enables it to be secreted to interstitial tissues, allowing it to transfer their malignant potential to nearby cells [39].…”

“…Previous studies have shown that glioblastomas express ASAH1 in high numbers. Doan et al demonstrated that irradiated cell culture and tumor tissues have higher expression levels of ASAH1 compared to non-irradiated culture and tumor tissues, therefore leading to apoptotic resistance and glioblastoma recurrence [38]. This led to the identification of overexpression of ASAH1 as a potential biomarker associated with glioblastomas and the development of anticancer therapy.…”

Targeting the Sphingolipid System as a Therapeutic Direction for Glioblastoma

“…Subsequent inhibition of acid ceramidase using N-oleoylethanolamine, was found to suppress this increase in ASAH1 expression, resulting in increased ceramide accumulation [149]. Elevated ASAH1 levels have been reported in the tumors of patients with newly diagnosed GBM, as well as radiotherapy-treated GBM, correlating with poor survival [165,166]. This elevation of ASAH1 in response to radiation has also been reported in both adult (U87) and pediatric (SJGBM-2) GBM cell lines, as well as patient tissue samples [165,166].…”

Heritable cognitive and psychopathology factors in youth are predicted by brain fronto-temporal white matter pathway

“…Probabilistic fiber tracking: Whole brain probabilistic fiber tracking was performed using probtrackx2 20 . In line with a recent application in aging and dementia 21 , for each participant and from each voxel inside the native space whole brain seed mask, 100 pathways were sampled, resulting in a 3D-volume tractography-map per participant which were normalized by dividing with the total number of streamlines processed. Thus, the value in each voxel represents the likelihood that any streamline will pass through that voxel (connection density).…”