Adenylate Kinase and Metabolic Signaling in Cancer Cells

Abstract

A hallmark of cancer cells is the ability to rewire their bioenergetics and metabolic signaling circuits to fuel their uncontrolled proliferation and metastasis. Adenylate kinase (AK) is the critical enzyme in the metabolic monitoring of cellular adenine nucleotide homeostasis. It also directs AK→ AMP→ AMPK signaling controlling cell cycle and proliferation, and ATP energy transfer from mitochondria to distribute energy among cellular processes. The significance of AK isoform network in the regulation of a variety of cellular processes, which include cell differentiation and motility, is rapidly growing. Adenylate kinase 2 (AK2) isoform, localized in intermembrane and intra-cristae space, is vital for mitochondria nucleotide exchange and ATP export. AK2 deficiency disrupts cell energetics, causes severe human diseases, and is embryonically lethal in mice, signifying the importance of catalyzed phosphotransfer in cellular energetics. Suppression of AK phosphotransfer and AMP generation in cancer cells and consequently signaling through AMPK could be an important factor in the initiation of cancerous transformation, unleashing uncontrolled cell cycle and growth. Evidence also builds up that shift in AK isoforms is used later by cancer cells for rewiring energy metabolism to support their high proliferation activity and tumor progression. As cell motility is an energy-consuming process, positioning of AK isoforms to increased energy consumption sites could be an essential factor to incline cancer cells to metastases. In this review, we summarize recent advances in studies of the significance of AK isoforms involved in cancer cell metabolism, metabolic signaling, metastatic potential, and a therapeutic target.

Keywords: adenylate kinase; cancer; energy metabolism; mitochondria; phosphotransfer.

Figure 1

Overview of adenylate kinase (AK) isoform involvement in the rewiring of cancer cell metabolic signaling and energetic circuits. Increased competition for cytosolic ADP downregulates AK-mediated AMP signaling, reducing control over cell cycle and proliferation. AK expression is downregulated in several tumors. AMP can be consumed by AMPD and by 5′-NT, also overexpressed in some cancer cells. Augmented glycolytic metabolism, owing to higher affinity, scavenges cytosolic ADP, and uses mitochondrial ATP to drive glucose conversion to lactate. Overexpression of glycolytic HK2, PKM2, and LDHA and mitochondrial ANT2, AK2, AK4, and other genes in cancer cells promotes rewiring of energetic circuits resulting in unrestrained energy distribution. The result of these metabolic transformations is deficient AMP signaling and AMPK-mediated control of cellular katabolic and anabolic processes. Red color indicates the augmented pathways and gene expression in cancer cells. AMPD, AMP-deaminase; HK2, hexokinase 2; LDHA, lactate dehydrogenase A; ANT2, adenine nucleotide translocase 2; AMPK, AMP-activated protein kinase.