Fructose 2,6-Bisphosphate in Cancer Cell Metabolism

Abstract

For a long time, pioneers in the field of cancer cell metabolism, such as Otto Warburg, have focused on the idea that tumor cells maintain high glycolytic rates even with adequate oxygen supply, in what is known as aerobic glycolysis or the Warburg effect. Recent studies have reported a more complex situation, where the tumor ecosystem plays a more critical role in cancer progression. Cancer cells display extraordinary plasticity in adapting to changes in their tumor microenvironment, developing strategies to survive and proliferate. The proliferation of cancer cells needs a high rate of energy and metabolic substrates for biosynthesis of biomolecules. These requirements are met by the metabolic reprogramming of cancer cells and others present in the tumor microenvironment, which is essential for tumor survival and spread. Metabolic reprogramming involves a complex interplay between oncogenes, tumor suppressors, growth factors and local factors in the tumor microenvironment. These factors can induce overexpression and increased activity of glycolytic isoenzymes and proteins in stromal and cancer cells which are different from those expressed in normal cells. The fructose-6-phosphate/fructose-1,6-bisphosphate cycle, catalyzed by 6-phosphofructo-1-kinase/fructose 1,6-bisphosphatase (PFK1/FBPase1) isoenzymes, plays a key role in controlling glycolytic rates. PFK1/FBpase1 activities are allosterically regulated by fructose-2,6-bisphosphate, the product of the enzymatic activity of the dual kinase/phosphatase family of enzymes: 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFKFB1-4) and TP53-induced glycolysis and apoptosis regulator (TIGAR), which show increased expression in a significant number of tumor types. In this review, the function of these isoenzymes in the regulation of metabolism, as well as the regulatory factors modulating their expression and activity in the tumor ecosystem are discussed. Targeting these isoenzymes, either directly or by inhibiting their activating factors, could be a promising approach for treating cancers.

Identification of a Subtype of Hepatocellular Carcinoma with Poor Prognosis Based on Expression of Genes within the Glucose Metabolic Pathway

“…PFKFB1 has not been well studied and not found to be overexpressed in cancer cells [37]. In contrast to our finding, PFKFB3 was reported to be constitutively overexpressed in different cancer cell lines, several human leukemias, and multiple solid tumors such as ovarian cancer, thyroid cancer, breast cancer, gastric tumors, and pancreatic cancer [37][38][39]. Its expression was found to be associated with lymph node metastasis and the TNM stage [39].…”

“…These PFKFB isoforms were also significantly associated with patient OS, and PFKFB1 was associated with an advanced tumor stage as well. PFKFB1 has not been well studied and not found to be overexpressed in cancer cells [37]. In contrast to our finding, PFKFB3 was reported to be constitutively overexpressed in different cancer cell lines, several human leukemias, and multiple solid tumors such as ovarian cancer, thyroid cancer, breast cancer, gastric tumors, and pancreatic cancer [37][38][39].…”

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

“…The second key rate-limiting glycolytic enzyme is PFK, a tetrameric enzyme in mammals that catalyzes the third reaction of glycolysis, that is, phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate (FBP) accompanied by ATP utilization. Interplay between HIF-1α and Ras/Src oncogenes in tumor microenvironment in the regulation of PFK1 and PFK2 isoenzymes has been suggested as being a contributor to human cancer cell proliferation and survival [94]. PFK1 is an allosteric enzyme activated by fructose-2,6-bisphosphate that is produced from fructose-6-phosphate by the bifunctional phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) family of enzymes, which is induced by HIF-1α.…”

A Sweet Connection? Fructose’s Role in Hepatocellular Carcinoma

“…Growth signals, such as epidermal growth factor receptor (EGFR), activate the PI3K/Akt signaling pathway and consequently increase glucose transporters (GLUT1) expression and the activity of PFK2 [130]. PFK2 phosphorylates fructose-6-phosphate (F6P) to generate fructose-2,6-biphosphate (F-2,6-BP), which promotes glycolysis by activating PFK1 and in turn inhibits gluconeogenesis through inhibiting FBP1 [130,131]. Hence, increased F-2,6-BP stimulates cancer cell glycolysis to fuel cell growth.…”

“…This is termed the "reverse Warburg effect", whereby anabolic cancer cells metabolically adapt to the tumor microenvironment and promote aerobic glycolysis in the neighboring stromal cells. The stromal cells produce lactate, fatty acids, amino acids, glutamine, and ketone bodies that are in turn used by the cancer cells to support growth [131,[133][134][135]. In response to metabolic stress, cancer cells may shift away from glycolysis and primarily utilize the PPP and mitochondrial oxidative phosphorylation as the primary means of obtaining energy, producing nucleotide precursors, and generating antioxidants to manage ROS.…”