Abstract
BackgroundCervical cancer (CC) is the second most common cancer among women with high morbidity and mortality. TKTL1 is a key protein in glucose metabolism in cancer cells and controls the pentose phosphate pathway (PPP). In this paper, we aim to explore whether TKTL1 can participate in the malignant process of CC cells through glucose metabolism.MethodsThe expression and activity of TKTL1 in CC cell lines were detected by RT-qPCR and Western blot. Cell transfection was conducted to interfere the expression of TKTL1 in SiHa cells, with efficiency detected by RT-qPCR and Western blot. Cell proliferation was then measured by CCK-8 kits. Wound Healing and Transwell experiments were performed to respectively detect the levels of cell migration and invasion, and western blot was used to detect the expressions of migration-related proteins. Tunel and Western blot were used to detect the apoptosis and apoptosis-related proteins. Glucose uptake, lactate production, and ATP production were measured by corresponding commercial kits. Next, the expression of p-Akt, AKT, p-MTOR, mTOR, HK2 and PFKFB3 was detected by Western blot. The mechanism was further investigated by interfering the expression of HK2 and PFKFB3 and adding AKT agonist SC79. At the animal level, the tumor bearing mouse model of CC was constructed, and the weight, volume and pathological morphology of the tumor tissue were detected to verify the cell experiment.ResultsTKTL1 expression was increased in CC cells. Interference of TKTL1 expression can inhibit TKTL1 enzyme activity, proliferation, invasion and migration of CC cells, and simultaneously suppress the generation of glycolysis. In addition, the results showed that TKTL1 activated PFKFB3 through AKT rather than HK2 signaling and is involved in glycolysis, cell invasion, migration, and apoptosis of CC cells. In animal level, inhibition of TKTL1 also contributed to decreased tumor volume of CC tumor bearing mice and improved histopathological status.ConclusionTKTL1 participated in malignant progression of CC cells via regulating AKT signal-mediated HK2 and PFKFB3 and thus regulating glucose metabolism.
Highlights
Cervical cancer (CC) is the second most common cancer among women [1]
TKTL1 interference inhibited the malignant progression of of CC cells The results of RT-qPCR and Western blot showed that TKTL1 expression in CC cell lines was abnormally increased (Fig. 1A and B)
The activity of TKTL1 in the cells was determined by enzymelinked assay, which showed a significant increase in TKTL1 activity in CC cells compared with End1/E6E7 cells (Fig. 1C)
Summary
Cervical cancer (CC) is the second most common cancer among women [1]. There are about 529,800 new diagnosed CC cases and 275,100 deaths from CC each year [2]. As an important branch of glucose metabolism, pentose phosphate pathway (PPP) plays an important role in biosynthesis and promotes the process and development of tumors [6, 7]. Studies have shown that TKTL1 is responsible for about 60–70% of TKT activity in human liver and colon cancer cells [11,12,13]. These results indicate that TKTL1 plays an important role in the regulation of tumor metabolism. TKTL1 is a key protein in glucose metabolism in cancer cells and controls the pentose phosphate pathway (PPP). We aim to explore whether TKTL1 can participate in the malignant process of CC cells through glucose metabolism
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