Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Nov 29;8(12):603.
doi: 10.3390/antiox8120603.

Metabolic Remodelling: An Accomplice for New Therapeutic Strategies to Fight Lung Cancer

Cindy Mendes  1   2 , Jacinta Serpa  1   2
Affiliations
Review

Metabolic Remodelling: An Accomplice for New Therapeutic Strategies to Fight Lung Cancer

Cindy Mendes et al. Antioxidants (Basel). .

Abstract

Metabolic remodelling is a hallmark of cancer, however little has been unravelled in its role in chemoresistance, which is a major hurdle to cancer control. Lung cancer is a leading cause of death by cancer, mainly due to the diagnosis at an advanced stage and to the development of resistance to therapy. Targeted therapeutic agents combined with comprehensive drugs are commonly used to treat lung cancer. However, resistance mechanisms are difficult to avoid. In this review, we will address some of those therapeutic regimens, resistance mechanisms that are eventually developed by lung cancer cells, metabolic alterations that have already been described in lung cancer and putative new therapeutic strategies, and the integration of conventional drugs and genetic and metabolic-targeted therapies. The oxidative stress is pivotal in this whole network. A better understanding of cancer cell metabolism and molecular adaptations underlying resistance mechanisms will provide clues to design new therapeutic strategies, including the combination of chemotherapeutic and targeted agents, considering metabolic intervenients. As cancer cells undergo a constant metabolic adaptive drift, therapeutic regimens must constantly adapt.

Keywords: cancer metabolism; lung cancer; new therapeutic strategies; reactive oxygen species (ROS); therapy resistance.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Metabolic remodelling in lung cancer. Metabolic pathways are involved in the synthesis of building blocks for macromolecules and redox homeostasis, needed for cell proliferation are presented. The import of glucose is mediated by the GLUT (glucose transporter) family of membrane transport proteins, which are known to be deregulated in cancer [34]. Hexokinase 2 (HK-2) is the first rate-limiting enzyme in the glycolytic pathway and overexpression of HK-2 has wildly been observed in cancer cells, correlating with poor overall survival in cancer patients [35,36,37]. Mutant EGFR (epidermal growth factor receptor 1) promotes metabolic remodelling in non-small-cell lung carcinoma (NSCLC) with increased aerobic glycolysis and PPP (pentose phosphate pathway), altered pyrimidine biosynthesis and upregulation of monounsaturated fatty acids [38,39,40]. KRAS (Kirsten rat sarcoma viral oncogene homolog GTPase)-mutated NSCLC cells express higher levels of enzymes involved in glycolysis, such as pyruvate kinase isozyme M2 (PKM2) and lactate dehydrogenase A (LDHA) compared with nonmalignant cells, indicating alterations in glucose metabolism and PPP (glicose-6-fosfato dehydrogenase (G6PD), transketolase (TKT) and 6-phosphogluconate dehydrogenase (6PGD)) [41]. Pyruvate is decarboxylated into acetyl-CoA to be further transported into mitochondria to enter the TCA cycle [42]. ALK (anaplastic lymphoma kinase) rearrangements were associated with upregulated glucose metabolism in highly metastatic phenotypes of adenocarcinoma [43]. The expression and activity of PC (pyruvate carboxylase), the enzyme responsible for the conversion of pyruvate into oxaloacetate, was found to be elevated in NSCLC tumours [28,33]. Glycolysis and glucose oxidation via PDH (pyruvate dehydrogenase) and the TCA cycle were enhanced in NSCLC comparing to adjacent benign lung [28]. Cancer cells also show higher levels of monocarboxylate transporters (MCT), which are responsible for lactate export and helps both in maintaining intracellular pH and in continuing glycolysis [44]. Hif-1 (hypoxia inducible factor 1) regulates the transcription of glycolytic enzymes such as, HK-2, LDH-A and PKM2, which upregulate glycolysis [45,46]. The expression of ATP citrate lyase (ACLY), a key enzyme in fatty acid synthesis was upregulated in NSCLC, being associated with poor prognosis [30]. Glutathione cysteine ligase (GCLC), which converts glutamate to Glutathione (GSH), is also highly expressed in several cancers, including lung cancer, and high mRNA expression of GCLC-promoted cisplatin resistance in lung adenocarcinoma cell lines [47]. G6P: glucose 6-phosphate; 3PG: 3-phosphoglyceric acid; PEP: phosphoenolpyruvate; R5P: ribose 5-phosphate; MCT: monocarboxylate transporters; OAA: oxaloacetate; α-KG: alpha ketoglutarate.
Figure 2
Figure 2
New metabolic therapies targeting drug-resistant lung cancer. The metabolic inhibitors that can be used to target drug-resistant cancers are shown in yellow. The sugar analogue 2-deoxyglucose (2-DG, competitive inhibitor of Hexokinase (HK), has been shown to be selectively cytotoxic to several tumour cell lines under anaerobic and/or hypoxic conditions [208,209] and to reduce resistance to cisplatin in lung cancer cells and an in vivo xenograft model of lung cancer [201]. Thus, 2-DG has the potential of being used clinically as an adjuvant to the classical chemotherapeutic compounds, such as cisplatin. Riluzole interferes with glutamate flux and was shown to increase reactive oxygen species (ROS) by suppressing lactate dehydrogenase A (LDHA) and NAD+ [197]. Glutamate stimulates the glutamine import and glutaminolysis, sustaining the import of cyst(e)ine, which has been related to increased therapy resistance in different cancer models [51], mostly due to its role in glutathione synthesis [52,54]. Riluzole interferes with system xCT-cystine/glutamate antiporter, resulting in decreased GSH levels [197]. Thus, using riluzole as an antitumour agent against cisplatin resistance in lung cancer patients could be further explored. Treatment with CB-389, a glutaminase inhibitor generated a metabolic crisis in EGFR mutant NSCLC cells, resulting in cell death and in rapid tumour regression in mouse NSCLC xenografts [64]. Metformin, an antidiabetic drug, was observed to increase the sensitivity of carboplatin-resistant NSCLC cells to carboplatin treatment in vitro and in vivo [210] and also reversed resistance to tyrosine kinase inhibitors (TKIs) and ALK inhibitors in lung cancer [211]. Another study demonstrated that metformin enhanced the sensitivity to a combined treatment of cisplatin and ionizing radiation in H460 and A549 NSCLC cell lines, with a greater effect in the A549 cell line, which is less sensitized by cisplatin [212]. Elesclomol is another potential therapeutic agent, since it further increased ROS in cisplatin-resistant cells, pushing them beyond their tolerance limit, which ultimately leads to cell death [199].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Cairns R.A., Mak T.W. The current state of cancer metabolism. Nat. Rev. Cancer. 2016;16:613–614. doi: 10.1038/nrc.2016.100. - DOI
    1. De Berardinis R.J., Chandel N.S. Fundamentals of cancer metabolism. Sci. Adv. 2016;2:e1600200. doi: 10.1126/sciadv.1600200. - DOI - PMC - PubMed
    1. Warburg O., Minami S. Versuche an Überlebendem Carcinomgewebe. Klin. Wochenschr. 1923;2:776–777. doi: 10.1007/BF01712130. - DOI
    1. Dang C.V. Links between metabolism and cancer. Genes. Dev. 2012;26:877–890. doi: 10.1101/gad.189365.112. - DOI - PMC - PubMed
    1. Koppenol W.H., Bounds P.L., Dang C.V. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat. Rev. Cancer. 2011;11:325–337. doi: 10.1038/nrc3038. - DOI - PubMed