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 Feb 2;20(3):644.
doi: 10.3390/ijms20030644.

Curbing Lipids: Impacts ON Cancer and Viral Infection

Anika Dutta  1 , Neelam Sharma-Walia  2
Affiliations
Review

Curbing Lipids: Impacts ON Cancer and Viral Infection

Anika Dutta et al. Int J Mol Sci. .

Abstract

Lipids play a fundamental role in maintaining normal function in healthy cells. Their functions include signaling, storing energy, and acting as the central structural component of cell membranes. Alteration of lipid metabolism is a prominent feature of cancer, as cancer cells must modify their metabolism to fulfill the demands of their accelerated proliferation rate. This aberrant lipid metabolism can affect cellular processes such as cell growth, survival, and migration. Besides the gene mutations, environmental factors, and inheritance, several infectious pathogens are also linked with human cancers worldwide. Tumor viruses are top on the list of infectious pathogens to cause human cancers. These viruses insert their own DNA (or RNA) into that of the host cell and affect host cellular processes such as cell growth, survival, and migration. Several of these cancer-causing viruses are reported to be reprogramming host cell lipid metabolism. The reliance of cancer cells and viruses on lipid metabolism suggests enzymes that can be used as therapeutic targets to exploit the addiction of infected diseased cells on lipids and abrogate tumor growth. This review focuses on normal lipid metabolism, lipid metabolic pathways and their reprogramming in human cancers and viral infection linked cancers and the potential anticancer drugs that target specific lipid metabolic enzymes. Here, we discuss statins and fibrates as drugs to intervene in disordered lipid pathways in cancer cells. Further insight into the dysregulated pathways in lipid metabolism can help create more effective anticancer therapies.

Keywords: PPAR; cancer; cholesterol; fatty acids; fibrates; statins; viruses.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Pathways that link breast cancer with obesity: Several consequences of obesity, such as insulin resistance, higher levels of circulating estrogen, and secreted cytokines play a role in the development of breast cancer. Insulin and IGF-1 promote proliferation and angiogenesis by activating the PI3K/Akt and Ras/Raf/MAPK pathways. Insulin also inhibits sex-hormone-binding globulin (SHBG), which binds testosterone and estradiol so there is increased free estradiol. Circulating estrogens promote growth of breast epithelial cells and lead to more proliferation and angiogenesis as well. Adipocytes can secrete pro-inflammatory cytokines which stimulate more lipolysis and further release of free fatty acids to promote cancer cell survival. T-bars in red denote inhibition.
Figure 2
Figure 2
Pathways that lead to an accumulation of cholesterol: Activation of SREBP transcription factor induces cholesterol. This is induced by activation of PI3K/Akt/mTOR signaling, cancer gene RAS, and dysregulation by TP53. The accumulation of cholesterol in the cell promotes survival and inhibits apoptosis. T-bar in red denotes inhibition.
Figure 3
Figure 3
Mevalonate pathway as an important metabolic pathway: The mevalonate pathway is regulated by HMG CoA reductase (HMGCR), and this enzyme is targeted by statins to decrease plasma cholesterol. Fibrates target the mevalonate pathway by inhibiting acetoacetyl coenzyme A. This reverses the effects of cholesterol to inhibit cell proliferation and trigger apoptotic parameters. Downregulating the pathway also suppresses production of farnesyl pyrophosphate and geranylgeranyl phosphate to inhibit the invasive properties of cancer cells. T-bars in red denote inhibition.
Figure 4
Figure 4
Triacylglycerols are synthesized from acetyl-CoA. Acetyl-coA is metabolized to malonyl-CoA via acetyl-CoA carboxylase, which in turn is converted to Palmitate, the principal product of the fatty acid synthase system in animal cells. Palmitate is lengthened to form stearate by enzyme fatty acid elongase. Stearate, a saturated fatty acid is subsequently metabolized by stearoyl-CoA desaturase enzyme, that forms a double bond in stearoyl-CoA, leading to the monounsaturated fatty acid oleic acid. Carnitine palmitoyltransferase (CPT), the enzyme in the outer mitochondrial membrane, converts long-chain acyl-CoA species to their corresponding long-chain acyl-carnitines for transport into the mitochondria. CPT induces mitochondrial β-oxidation, which is a complex pathway involving energy metabolism. FASN inhibits CPT with resultant inhibition of fatty acid oxidation. T-bar in red denotes inhibition.
Figure 5
Figure 5
Fatty acid synthase (FASN) levels in human breast cancer tissue samples. 16 breast cancer tissue samples, in duplicates (A,B,D,E) along with their controls (C,F) were analyzed by IHC staining for FASN. Magnification for the panels is 4×.
Figure 6
Figure 6
Fatty acid deregulation in pathogenesis of human cancer: A key lipogenic enzyme in fatty acid is fatty acid synthase (FASN), which can be inhibited to downregulate fatty acid synthase to inhibit DNA replication and arrest cell growth.
Figure 7
Figure 7
Arachidonic acid cascade: Arachidonic acid is a fatty acid that is freed from cellular membranes by phospholipase A2. It can then be metabolized to prostanoids such as thromboxanes (TXA2), prostacyclin (PGI2) and prostaglandins PGD2, PGE2, and PGF2a through the cyclooxygenase (COX) pathway. The lipoxygenase (LO) pathway along with hydrolases converts arachidonic acid into leukotrienes, hydroxyeicosatetraenoic acids (HETEs), and lipoxins (LXA4 and LXB4). Lastly, the cytochrome P450 monooxygenase pathway converts arachidonic acid into epoxyeicosatrienoic acids (EETs).
Figure 8
Figure 8
Statin therapy and downstream consequences: Statins block transcription of NFkB. This decreases expression of anti-apoptotic BclXL and inhibits cancer cell proliferation. Inhibition of NFkB also increases expression of pro-apoptotic phosphatase and tensin homolog (PTEN). PTEN inhibits PI3 kinase, and therefore also inhibits the target of PI3 kinase, Akt kinase, which are both associated with the anti-apoptotic properties of cancer cells. T-bars in red denote inhibition.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Zali H., Rezaei-Tavirani M., Azodi M. Gastric cancer: Prevention, risk factors and treatment. Gastroenterol. Hepatol. Bed Bench. 2011;4:175–185. - PMC - PubMed
    1. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2018. CA Cancer J. Clin. 2018;68:7–30. doi: 10.3322/caac.21442. - DOI - PubMed
    1. Dela Cruz C.S., Tanoue L.T., Matthay R.A. Lung cancer: Epidemiology, etiology, and prevention. Clin. Chest Med. 2011;32:605–644. doi: 10.1016/j.ccm.2011.09.001. - DOI - PMC - PubMed
    1. Ahern T.P., Pedersen L., Tarp M., Cronin-Fenton D.P., Garne J.P., Silliman R.A., Sorensen H.T., Lash T.L. Statin prescriptions and breast cancer recurrence risk: A Danish nationwide prospective cohort study. J. Natl. Cancer Inst. 2011;103:1461–1468. doi: 10.1093/jnci/djr291. - DOI - PMC - PubMed
    1. Haggar F.A., Boushey R.P. Colorectal cancer epidemiology: Incidence, mortality, survival, and risk factors. Clin. Colon Rectal Surg. 2009;22:191–197. doi: 10.1055/s-0029-1242458. - DOI - PMC - PubMed

MeSH terms