L-Carnitine–Mediated Tumor Cell Protection and Poor Patient Survival Associated with OCTN2 Overexpression in Glioblastoma Multiforme

Abstract

Purpose: Apoptotic dysregulation, redox adaptive mechanisms, and resilience to hypoxia are major causes of glioblastoma (GBM) resistance to therapy. Commonly known as crucial factors in energy metabolism, OCTN2 (SLC22A5) and its substrate L-carnitine (LC) are increasingly recognized as actors in cytoprotection. This study provides a comprehensive expression and survival analysis of the OCTN2/LC system in GBM and clarifies the system's impact on GBM progression.Experimental Design: OCTN2 expression and LC content were measured in 121 resected human GBM specimens and 10 healthy brain samples and analyzed for prognostic significance. Depending on LC administration, the effects of hypoxic, metabolic, and cytotoxic stress on survival and migration of LN18 GBM cells were further studied in vitro. Finally, an orthotopic mouse model was employed to investigate inhibition of the OCTN2/LC system on in vivo GBM growth.Results: Compared with healthy brain, OCTN2 expression was increased in primary and even more so in recurrent GBM on mRNA and protein level. High OCTN2 expression was associated with a poor overall patient survival; the unadjusted HR for death was 2.7 (95% CI, 1.47-4.91; P < 0.001). LC administration to GBM cells increased their tolerance toward cytotoxicity, whereas siRNA-mediated OCTN2 silencing led to a loss of tumor cell viability. In line herewith, OCTN2/LC inhibition by meldonium resulted in reduced tumor growth in an orthotopic GBM mouse model.Conclusions: Our data indicate a potential role of the OCTN2/LC system in GBM progression and resistance to therapy, and suggests OCTN2 as a prognostic marker in patients with primary GBM.

Carnitine Traffic in Cells. Link With Cancer

“…To date, several studies reported a link between the altered expression of OCTN2 and cancer development and progression (Lu et al, 2008;Scalise et al, 2012;Wang et al, 2012;Elsnerova et al, 2016;Lee et al, 2016;Fink et al, 2019;Juraszek and Nalecz, 2019; Table 1). Interestingly, its expression is found up or down-regulated depending on the carbon source that the tumors use to produce energy.…”

SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer

“…Interestingly, the fatty acid oxidation enzymes (including CPT1a) were also detected in glioma cells and the process of fatty acid oxidation contributed significantly to their aerobic respiration, while treatment with etomoxir decreased cell proliferation and prolonged survival in the mouse model of this disease [88]. Moreover, OCTN2 expression was increased in primary glioblastoma samples from patients, and even more so in samples from patients with recurrent glioblastoma, when compared to the healthy brain [89].…”

Synergistic Effect of Dietary Betaines on SIRT1-Mediated Apoptosis in Human Oral Squamous Cell Carcinoma Cal 27

“…A deeper knowledge of the biological basis of the antitumor effects of δVB is tempting, especially in light of the possible mechanism of action of δVB occurring through the reduction of l-carnitine uptake by inhibiting the organic l-carnitine cation transporter type 2 [12], known to have an altered expression in several cancer cell lines. In particular, this mechanism may take part to an alternative to glucose source of energy for cancer cells growth and proliferation by supplying l-carnitine for β-oxidation [23,24]. The present study aimed at evaluating the possible anticancer effects of milk betaines in oral squamous cell carcinomas [25].…”