Unraveling the Mystery of Energy-Sensing Enzymes and Signaling Pathways in Tumorigenesis and Their Potential as Therapeutic Targets for Cancer - Review

Sep 21, 2026

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Cancer research has accelerated through the discovery of causative genes, proteins, and signaling pathways, yet developing target-specific anticancer drugs with minimal side effects remains difficult. Increasing attention has turned to energy-sensing and homeostasis-associated molecules that regulate proliferation, apoptosis, autophagy, and angiogenesis. Energy metabolism studies highlight heightened glycolysis and reduced oxidative phosphorylation in tumor cells, consistent with the Warburg effect. Energy homeostasis is essential for normal and malignant survival, making disruption of glycolysis and nucleotide/metabolite levels promising targets. This review summarizes energy mediators and sensors, their mechanisms and related pathways in carcinogenesis, and evaluates the potential for drug discovery by inhibiting tumor energy metabolism, supported by transcriptomic meta-analysis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages22

Reading Time55 min

AccessFree to download

Introduction

Energy homeostasis and cancer hallmarks

Cancer metabolism and ATP balance

Energy-linked metabolic changes and therapeutic potential

cells Review Unraveling the Mystery of Energy-Sensing Enzymes and Signaling Pathways in Tumorigenesis and Their Potential as Therapeutic Targets for Cancer Zeenat Mirza 1,2, * and Sajjad Karim 2,3 Citation: Mirza, Z.; Karim, S. Unraveling the Mystery of EnergySensing Enzymes and Signaling Pathways in Tumorigenesis and Their Potential as Therapeutic Targets for Cancer. Cells 2024, 13, 1474. [https://](https://)[ ](https://)[doi.org/10.3390/cells13171474](doi.org/10.3390/cells13171474) Academic Editor: Valentina De Falco Received: 6 June 2024 Revised: 27 July 2024 Accepted: 30 July 2024 Published: 2 September 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21587, Saudi Arabia 2 Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21587, Saudi Arabia; [skarim1@kau.edu.sa](skarim1@kau.edu.sa) 3 Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21587, Saudi Arabia * Correspondence: [zmirza1@kau.edu.sa](zmirza1@kau.edu.sa) Abstract: Cancer research has advanced tremendously with the identification of causative genes, proteins, and signaling pathways. Numerous antitumor drugs have been designed and screened for cancer therapeutics; however, designing target-specific drugs for malignant cells with minimal side effects is challenging. Recently, energy-sensing-and homeostasis-associated molecules and signaling pathways playing a role in proliferation, apoptosis, autophagy, and angiogenesis have received increasing attention. Energy-metabolism-based studies have shown the contribution of energetics to cancer development, where tumor cells show increased glycolytic activity and decreased oxidative phosphorylation (the Warburg effect) in order to obtain the required additional energy for rapid division. The role of energy homeostasis in the survival of normal as well as malignant cells is critical; therefore, fuel intake and expenditure must be balanced within acceptable limits. Thus, energy-sensing enzymes detecting the disruption of glycolysis, AMP, ATP, or GTP levels are promising anticancer therapeutic targets. Here, we review the common energy mediators and energy sensors and their metabolic properties, mechanisms, and associated signaling pathways involved in carcinogenesis, and explore the possibility of identifying drugs for inhibiting the energy metabolism of tumor cells. Furthermore, to corroborate our hypothesis, we performed meta-analysis based on transcriptomic profiling to search for energy-associated biomarkers and canonical pathways. Keywords: cancer; energy-sensing enzymes; genes and signaling pathways; Warburg effect; anticancer drug 1. Introduction Cancer, as a leading health problem globally, was diagnosed in an estimated 19.3 million new cases and accounted for approximately 10 million deaths in 2020; it is projected that it will be responsible for an estimated 13.1 million deaths in 2030 [1,2] . Cancer originates intracellularly due to genetic changes, mostly involving activated oncogenes or defective tumor suppressor genes, leading to the development of multiple cancer hallmarks, such as unrestrained growth and resistance to pro-death and antigrowth signals [3–5] . The conversion of normal cells into malignant cells and tumors progresses through multiple steps that have been categorized into six established hallmarks, including (i) proliferative signaling,(ii) escaping growth suppressors,(iii) resisting apoptosis,(iv) allowing replicative immortality,(v) triggering angioge

FAQs

Why are target-specific anticancer drugs difficult to design?

Target-specific drug design for malignant cells with minimal side effects is challenging despite advances in antitumor drug development and screening.

How does the Warburg effect relate to energy-sensing enzymes as targets?

Tumor cells often show increased glycolytic activity and decreased oxidative phosphorylation to meet rapid energy needs, linking disrupted energy metabolism to potential anticancer targets.

What does the review cover regarding energy sensors and signaling pathways?

It reviews common energy mediators and energy sensors, their metabolic properties, mechanisms, and associated signaling pathways in carcinogenesis, and explores identifying drugs that inhibit tumor energy metabolism.

Sep 21, 2026

Upload by Miles