Glucose transporter 1 regulates the proliferation and cisplatin sensitivity of esophageal cancer

Abstract

Glucose transporter 1 ( GLUT 1) expression is a prognostic marker for esophageal squamous cell carcinoma ( ESCC ). Recent work on GLUT 1 and development of specific inhibitors supports the feasibility of GLUT 1 inhibition as a treatment for various cancers. The anti–proliferative effects of GLUT 1‐specific small interfering RNA (si RNA ) and a GLUT 1 inhibitor were evaluated in ESCC cell lines. Expression of pro–proliferative and anti–proliferative signaling and effector molecules was examined by western blotting and quantitative RT ‐ PCR . GLUT 1 expression in pretreatment clinical biopsy samples was measured by immunohistochemistry and correlated with various clinicopathological parameters and response to chemotherapy. The reduction in standardized uptake value ( SUV ) of 18 F‐fluoro‐deoxyglucose was calculated using the formula: ([pretreatment SUV max – posttreatment SUV max ]/pretreatment SUV max ) × 100. GLUT 1‐specific si RNA expression in ESCC cells inhibited their proliferation, increased expression of p27kip, and decreased expression of cyclin‐dependent kinase 6, pyruvate kinase muscle isozyme M2, lactate dehydrogenase A and phospho‐ ERK 1/2. Suppression of GLUT 1 by si RNA increased low‐dose cisplatin‐induced inhibition of proliferation of TE ‐11 ESCC cells, which express high GLUT 1 levels. Similarly, BAY ‐876, a GLUT 1 inhibitor, enhanced cisplatin‐mediated inhibition of ESCC cell proliferation. GLUT 1 expression in pretreatment biopsy samples was associated with the response to chemotherapy as well as the pathological tumor stage and histological response grade after esophagectomy. Finally, GLUT 1‐negative tumors showed a significantly larger reduction in SUV max (61.2% ± 4.5%) compared with GLUT 1‐positive tumors (46.2% ± 4.4%). GLUT 1 expression may be a surrogate marker of response to chemotherapy, and inhibition of GLUT 1 may be a potential novel therapy for ESCC patients.

Small‐Molecule Inhibition of Glucose Transporters GLUT‐1–4

“…WZB117 has also been successfully applied together with 5‐fluorouracil on resistant colon carcinomas (HCT116), which can be most probably explained with an observed GLUT‐1 upregulation in 5‐fluorouracil‐resistant and ‐treated colon cells . The GLUT‐1‐selective inhibitor BAY‐876 enhanced the response of cisplatin‐treated esophageal squamous cell carcinoma with respect to cell proliferation . Radiation of a tumor acts through creating double‐strand breaks in DNA as well as through cellular water radiolysis, which creates ROS .…”

“…However, care should be taken when selecting an appropriate cell line. BAY‐876 has been successfully applied to esophageal squamous cancer cell lines TE‐8 and TE‐11 in combination with cisplatin …”

“…BAY-876 has been successfully applied to esophageal squamous cancer cell lines TE-8 andT E-11i nc ombinationw ith cisplatin. [25] Kadmon reported ad ifferent class of glucoseu ptake inhibitors. [26] Example 31 in the corresponding patent (Figure2)i nhibited glycolytic ATPg eneration in HT1080 cells that were treated with oligomycin (inhibitor of mitochondrial complexV; Ta ble 1).…”

“…[18p] The GLUT-1-selective inhibitor BAY-876 enhanced the response of cisplatin-treated esophageal squamous cell carcinomaw ith respect to cell proliferation. [25] Radiation of at umor acts through creating double-strand breaksi nD NA as well as through cellular water radiolysis, which creates ROS. [41] Hence, ac ombinatorial treatment of radiotherapy and glucose uptake inhibition might offer ap romising opportunity to target cancerm ore efficiently.…”

Polymorphisms in Glycolysis-Related Genes Are Associated with Clinical Outcomes of Paclitaxel-Cisplatin Chemotherapy in Non-Small Cell Lung Cancer

“…Studies have revealed that enhanced glycolysis is associated with aggressiveness and poor prognosis in multiple cancers [16][17][18]. Accumulating data have also indicated that elevated aerobic glycolysis in cancer cells is critical for chemoresistance [18][19][20]. Taken together, the diverse roles of aerobic glycolysis in cancer suggest that alterations in the glycolytic pathway may influence chemotherapy outcomes.…”