Roles for hENT1 and dCK in gemcitabine sensitivity and malignancy of meningioma

Abstract

Background High-grade meningiomas are aggressive tumors with high morbidity and mortality rates that frequently recur even after surgery and adjuvant radiotherapy. However, limited information is currently available on the biology of these tumors and no alternative adjuvant treatment options exist. Although we previously demonstrated that high-grade meningioma cells were highly sensitive to gemcitabine in vitro and in vivo, the underlying molecular mechanisms remain unknown. Methods We examined the roles of hENT1 and dCK in the gemcitabine sensitivity and growth of meningioma cells in vitro. Tissue samples from meningiomas (26 WHO grade I and 21 WHO grade II/III meningiomas) were immunohistochemically analyzed for hENT1 and dCK as well as for Ki-67 as a marker of proliferative activity. Results hENT1 and dCK, which play critical roles in the intracellular transport and activation of gemcitabine, respectively, were responsible for the high gemcitabine sensitivity of high-grade meningioma cells and were strongly expressed in high-grade meningiomas. hENT1 expression was required for the proliferation and survival of high-grade meningioma cells and dCK expression. Furthermore, high hENT1 and dCK expression levels correlated with stronger tumor cell proliferative activity and shorter survival in meningioma patients. Conclusions The present results suggest that hENT1 is a key molecular factor influencing the growth capacity and gemcitabine sensitivity of meningioma cells and also that hENT1, together with dCK, may be a viable prognostic marker for meningioma patients as well as a predictive marker of their responses to gemcitabine.

Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins

“…IOMM-Lee and HKBMM, human malignant meningioma cell lines, were obtained from the American Type Culture Collection (Manassas, VA, USA) and from the Riken BioResource Center (Tsukuba, Japan), respectively. Their characteristics as malignant meningioma cells were confirmed in a previous study [ 8 ]. IOMM-Lee cells were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% fetal bovine serum (FBS).…”

“…We recently reported that gemcitabine, a pyrimidine anti-metabolite chemotherapeutic drug, was very effective for high-grade meningiomas, which highly express hENT1 and dCK, a transporter and rate-limiting kinase for gemcitabine, respectively [ 7 , 8 ]. Accordingly, the guidelines of the European Association of Neuro-Oncology (EANO) listed gemcitabine as one of the candidate drugs for the treatment of meningioma [ 3 ].…”

Gemcitabine radiosensitization primes irradiated malignant meningioma cells for senolytic elimination by navitoclax

“… 9 Furthermore, we recently demonstrated that high-grade meningiomas expressed high levels of human equilibrative nucleoside transporter 1 (hENT1) and deoxycytidine kinase (dCK), which play critical roles in the cellular uptake and activation of gemcitabine, respectively, and also that high-grade meningioma cells expressing hENT1 and dCK at high levels, including malignant meningioma cells, were sensitive to gemcitabine both in vitro and in vivo. 10 In support of these findings, a recent study reported that gemcitabine administered to a small number of patients with recurrent meningiomas on compassionate grounds achieved excellent outcomes, which underscores its potential as a therapeutic agent for aggressive meningiomas and has also led to the commencement of a clinical trial to evaluate its efficacy for recurrent high-grade meningiomas. 11 In addition to its efficacy as a single agent, gemcitabine has been shown to act as a radiosensitizer in tumor cells both in vitro and in vivo.…”

“…The intracranial implantation of IOMM-Lee cells was performed as previously described. 10 Briefly, after 5-week-old male BALB/cAjcl- nu/nu mice (CLEA, Japan) had been anesthetized and fixed in a stereotactic frame (Narishige, Tokyo, Japan), a burr hole was made in the parietal bone 2 mm posterior and 2 mm lateral to the bregma. IOMM-Lee cells suspended in PBS (2 × 10 5 in 2 µL) were intracranially implanted through the burr hole 4.0 mm below the skull surface with a 25-µL Hamilton syringe (Hamilton, Reno, NV, USA) that was mounted onto the stereotactic frame.…”

LncRNA SNHG6 Upregulates KPNA5 to Overcome Gemcitabine Resistance in Pancreatic Cancer via Sponging miR-944

“…GEM is a synthetic nucleoside analog that discontinues DNA synthesis. GEM enters cells via equilibrative and concentrative nucleoside transporters (hENTs and hCNTs), while hENT1 plays a key role in GEM uptake [ 5 ]. After entering the cell, GEM is phosphorylated to its main active metabolite 2′,2′-difluorodeoxycytidine triphosphate (dFdCTP) by deoxycytidine kinase; therefore, it competes with deoxycytidine triphosphate and takes action to inhibit DNA polymerase [ 6 ].…”