TKTL1 participated in malignant progression of cervical cancer cells via regulating AKT signal mediated PFKFB3 and thus regulating glycolysis

Abstract

Background Cervical 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. Methods The 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. Results TKTL1 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. Conclusion TKTL1 participated in malignant progression of CC cells via regulating AKT signal-mediated HK2 and PFKFB3 and thus regulating glucose metabolism.

Comprehensive analysis of hypoxia-related gene signature in cervical cancer

“…This metabolic switch provides an advantageous supply of material and energy substrate for tumor cell growth, enabling them to survive hypoxic environments. Studies have shown that transketolase like 1 (TKTL1) accelerates the malignant process of CC cells by participating in glycolysis [21]. Myosin 1B (MYO1B) activates the extracellular regulated protein kinases (ERK)/HIF-1A pathway and its downstream glycolysis-related genes, promoting glycolysis, migration and invasion, thus promoting the malignant progression of CC [22].…”

Upregulation of FAM83F by c-Myc promotes cervical cancer growth and aerobic glycolysis via Wnt/β-catenin signaling activation

“…Glycolysis has been associated with CC cell proliferation and apoptosis [ 43 , 44 ]. Interestingly, glycolysis was related to the expression of FAM83F [ 29 ].…”

Glucose metabolism reprogramming in gynecologic malignant tumors

“…This activation leads to increased glucose consumption, lactate secretion and ATP production. Inactivation of the Akt pathway by targeting these molecules could suppress the malignant process 49 , 50 . HR-HPV infection negatively regulates miR-155-5p expression while activating Akt/mTOR signaling to promote glycolytic flow.…”