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.

Energy Metabolic Plasticity of Colorectal Cancer Cells as a Determinant of Tumor Growth and Metastasis

“…AMP! AMPK signaling could lead to loss of control over the cell cycle, growth, and proliferation (124). A recent in-depth review about AKs and metabolic signaling in cancer cells by Klepinin et al (124) highlights the role of suppression of AK phosphotransfer and signaling through AMPK as a potential target for cancer metabolism.…”

“…In addition to their role in energy transfer among cellular processes, AKs are an integral part of intracellular energy sensing and metabolic signaling ( 123 , 124 ). Due to its catalytic reaction (2ADP ↔ AMP + ATP), it can amplify a small change in the ATP/ADP ratio into relatively large changes in AMP concentration.…”

“…The role of AMPK in cancer is controversial; it has been recognized as a tumor suppressor in some cancers ( 126 – 129 ) and in some cases described as a contextual oncogene, as the AMPK activation promotes tumor progression and chemoresistance ( 130 – 132 ). Downregulation of AK→ AMP→ AMPK signaling could lead to loss of control over the cell cycle, growth, and proliferation ( 124 ). A recent in-depth review about AKs and metabolic signaling in cancer cells by Klepinin et al.…”

“…A recent in-depth review about AKs and metabolic signaling in cancer cells by Klepinin et al. ( 124 ) highlights the role of suppression of AK phosphotransfer and signaling through AMPK as a potential target for cancer metabolism. How different AK isoforms are distributed in CRC cells and how their activities affect AMPK activation and metabolic plasticity need further investigation.…”

Assessing the Interactions of Statins with Human Adenylate Kinase Isoenzyme 1: Fluorescence and Enzyme Kinetic Studies

“…Adenylate kinases (AK, EC 2.7.4.3) are phosphotransferases regulating the nucleotide homeostasis and energetic metabolism via catalyzing the reversible phosphoryl transfer as follows: MgATP 2− + AMP 2− <=> MgADP − + ADP 3− [ 38 , 39 ]. In the past decade, a growing body of evidence indicate a novel prognostic and therapeutic potential of adenylate kinases in various medical conditions [ 40 , 41 ]. Nonetheless, no substantial attention has been paid so far to elucidate regulatory mechanisms of the AK function and identify drugs targeting these enzymes, which could expand their clinical relevance.…”