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Review
. 2024 Sep 2;13(17):1474.
doi: 10.3390/cells13171474.

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

Zeenat Mirza  1   2 , Sajjad Karim  2   3
Affiliations
Review

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

Zeenat Mirza et al. Cells. .

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: Warburg effect; anticancer drug; cancer; energy-sensing enzymes; genes and signaling pathways.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The tumor microenvironment pathway is predicted to be altered (z-score = −2.77) and closely associated [−log(p-value) = 8.83] with breast cancer. Description: AKT activates NFκB and SLC2 and inhibits BAD and FOXO via phosphorylation, where BAD and FOXO induce the apoptosis of tumor cells. ARG1 contributes to CD8 T-cell immunity; BCL2 promotes the survival of tumor cells; CCL2, CSF1, CSF2, and CSF3 enhance myeloid-derived suppressor cell accumulation and the proliferation of tumor-associated macrophages; CCND1 stimulates the proliferation of tumor cells; CD274 is responsible for the adaptive immune response of CD8+ T cells; CTL promotes apoptosis; and PD-1 is involved in the PD-L1 cancer immunotherapy pathway. CXCL12, CFCL8, FGF, MMP9, OSM, and VEGF are causative for angiogenesis. STAT3 regulates the expression of BCL2, CCND1, CD274, FAS, HIF1A, MMP2, MYC, PTGS2, SPP1, and VEGF, whereas NFκB regulates the expression of AP1, BCL2, CD274, CFLAR, and PLAU, which are responsible for tumor cell proliferation, viability, angiogenesis, and metastasis.
Figure 2
Figure 2
Mitochondrial biogenesis pathways. Downregulation of differentially expressed genes ACSS2, CHD9, IDH2, SOD2, MEF2C, PPARA, PPARGC1A, and PPARGC1B causes inhibition of the mitochondrial biogenesis process in breast cancer.
Figure 3
Figure 3
Integration of energy metabolism includes multiple events and pathways such as glucagon signaling in metabolic pathways, PKA-mediated phosphorylation, insulin stimulating increased expression of xylulose-5-phosphate (Xy-5-P), the AMP kinase (AMPK)-mediated response to elevated AMP, dephosphorylation of key metabolic factors by PP2A, and the transcriptional activation of metabolic genes by ChREBP.
Figure 4
Figure 4
Sirtuin signaling pathway. Description: NAD+ activates SIRT1–SIRT7. SIRT1 converts NAD+ to NAM. SIRT1 activates ATG, Clock-Bmal1, DOT1L, EPAS1, FOXO1, FOXO3, FOXO4, HSF1, Histone H1, Histone H3, Histone H4, NAMPT, NBN, NDRG1, NFE2L2, NOS3, NR1H4, Nr1h, PPARA, PPARGC1A, RARB, STK11, SUV39H1, TRIM28, WRN, XPA, XPC, XRCC6, and ZBTB14 and inhibits CRTC2, DUSP6, E2F1, FOXO3, HIF1A, NFκB, PPARG, SREBF1, STAT3, TP53, Trp73, and UCP2. Solid and dashed lines indicate direct and indirect relationship, respectively. The predicted relationships are denoted by different colors, wherein orange means “leads to activation”; blue indicates “leads to inhibition”; yellow implies that findings are inconsistent with the state of downstream molecules, and grey depicts that the effect is not predicted.
Figure 5
Figure 5
AMPK signaling pathway. AMPK activates AKT, MAP2K3, MLYCD, NAD+, PCAF-SWI/SNF, PFKFB, PI3K, SLC2A1, SLC2A4, and Tsc1-Tsc2 and inhibits ACC, CFTR, CRTC2, ELAVL1, FASN, glycogen synthase, HMGCR, HNF4A, LIPE, PPAT, and TBC1D1 via the phosphorylation of ACC, AKT, EEF2K, EP300, glycogen synthase, MLYCD, PFKFB, and PPAT. MTOR activates EIF4EBP1 and RPS6KB1 and inhibits ULK1 via phosphorylation. ULK1 induces autophagy. EEF2 is activated upon phosphorylation by EEF2K, which induces protein elongation. NOS3 is activated following phosphorylation by AKT1, promoting angiogenesis.
Figure 6
Figure 6
ERK/MAPK signaling pathway. Description: MAP2K1/2 activates ERK1/2 via phosphorylation. ERK1/2 activates Cpla2, ion channels, MAPKAPK5, and MKNK and inhibits SOS via phosphorylation, whereas the ERK1/2 dimer activates ELK1, ESR1, ETS, MSK1/2, STAT1/3, and c-Myc/N-Myc and inhibits PPARG via phosphorylation. Transcription is induced by ATF1, c-Myc/N-Myc, CREB, ELK1, ESR1, ETS, FOS, Histone H3, NFATC1, PPARG, SRF, Stat1/3, and EIF4E.
Figure 7
Figure 7
PI3K/AKT signaling pathway. AKT activates nitric oxide through NOS3 and promotes vasodilation and angiogenesis. AKT interacts with CDKN1B, MAP3K8, MAPK8IP1, MDM2, and RAF1 proteins to form complexes and inhibits BAD, FKHR, GSK3, MAP3K5, MAPK8IP1, RAF1, and TSC1/2 to promote cell survival and growth, cell cycle progression, energy storage, protein synthesis, vasodilation, and angiogenesis.
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