Clinical relevance of cholesterol homeostasis genes in colorectal cancer

Sharma, Bhoomika; Gupta, Vikas; Dahiya, Divya; Kumar, Hemanth; Vaiphei, Kim; Agnihotri, Navneet

doi:10.1016/j.bbalip.2019.06.008

Cited by 39 publications

(25 citation statements)

References 33 publications

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“…They showed that LXR activation resulted in ABC-G5/G8 mRNAs overexpression and CHOL efflux from hepatocytes and enterocytes. In contrast, significant downregulation of the LXR and ABCB1 in the early stage of CRCs is associated with the accumulation of CHOL within tumor cells, and subsequently promotes the initial phase of CRCs development [24]. In support of our data, the stimulation of LXR in CSCs increased ABC transporters, leading to tumoricidal effects on CSCs.…”

Section: Discussionsupporting

confidence: 84%

Modulation of LXR signaling altered the dynamic activity of human colon adenocarcinoma cancer stem cells in vitro

et al. 2021

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Background The expansion and metastasis of colorectal cancers are closely associated with the dynamic growth of cancer stem cells (CSCs). This study aimed to explore the possible effect of LXR (a regulator of glycolysis and lipid hemostasis) in the tumorgenicity of human colorectal CD133 cells. Methods Human HT-29 CD133+ cells were enriched by MACS and incubated with LXR agonist (T0901317) and antagonist (SR9243) for 72 h. Cell survival was evaluated using MTT assay and flow cytometric analysis of Annexin-V. The proliferation rate was measured by monitoring Ki-67 positive cells using IF imaging. The modulation of LXR was studied by monitoring the activity of all factors related to ABC transporters using real-time PCR assay and western blotting. Protein levels of metabolic enzymes such as PFKFB3, GSK3β, FASN, and SCD were also investigated upon treatment of CSCs with LXR modulators. The migration of CSCs was monitored after being exposed to LXR agonist using scratch and Transwell insert assays. The efflux capacity was measured using hypo-osmotic conditions. The intracellular content of reactive oxygen species was studied by DCFH-DA staining. Results Data showed incubation of CSCs with T0901317 and SR9243 reduced the viability of CD133 cells in a dose-dependent manner compared to the control group. The activation of LXR up-regulated the expression and protein levels of ABC transporters (ABCA1, ABCG5, and ABCG8) compared to the non-treated cells (p < 0.05). Despite these effects, LXR activation suppressed the proliferation, clonogenicity, and migration of CD133 cells, and increased hypo-osmotic fragility (p < 0.05). We also showed that SR9243 inhibited the proliferation and clonogenicity of CD133 cells through down-regulating metabolic enzymes PFKFB3, GSK3β, FASN, and SCD as compared with the control cells (p < 0.05). Intracellular ROS levels were increased after the inhibition of LXR by SR9243 (p < 0.05). Calling attention, both T0901317 and SR9243 compounds induced apoptotic changes in cancer stem cells (p < 0.05). Conclusions The regulation of LXR activity can be considered as a selective targeting of survival, metabolism, and migration in CSCs to control the tumorigenesis and metastasis in patients with advanced colorectal cancers.

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Section: Discussionsupporting

confidence: 84%

Modulation of LXR signaling altered the dynamic activity of human colon adenocarcinoma cancer stem cells in vitro

et al. 2021

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“…NR1H3 expression was significantly correlated to better survival in completely resected stages II and III NSCLC patients (164). Moreover, one study reports that NR1H3 and NR1H2 belong to a transcription signature associated with poor CRC clinical outcome independent of lymph node metastasis, distant metastasis, and advanced stage (156). This result is validated in TCGA dataset ( Table 1) where NR1H2 was also associated with CRC poor prognosis.…”

Section: Lipid-related Transcription Factor Alterations As Biomarkersmentioning

confidence: 69%

“…The combined expression of sterol regulatory elementbinding protein 2 (SREBP2) together with HMGCR, NR1H3, and NR1H2 genes was associated with poor CRC clinical outcome independent of lymph node metastasis, distant metastasis, and advanced stage (156). Besides, expression of SREBP-2 was elevated in advanced pathologic grade and metastatic prostate cancer and significantly associated with poor clinical outcomes (157).…”

Section: Lipid-related Transcription Factor Alterations As Biomarkersmentioning

confidence: 99%

Alterations of Lipid Metabolism in Cancer: Implications in Prognosis and Treatment

2020

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“…Cholesterol, as an essential component of the cell membrane, alters the biophysical properties of the membrane by governing its fluidity and impacts various biochemical functions, including modulation of signaling pathways and intercellular communication, as an integral component of lipid rafts ( 71 , 72 ). Cholesterol homeostasis involves the interplay between de novo synthesis, uptake of dietary cholesterol (low density lipoprotein – LDL or high density lipoprotein – HDL), and removal of excess cholesterol from peripheral tissues ( 73 ) ( Figure 1 ). In cancer, the reprogramed cholesterol metabolism can provide a signal transduction platform and activate stemness and oncogenic signaling (such as the Hedgehog pathway, mTORC1) as a second messenger or component of lipid rafts, thereby contributing to cancer progression and invasion ( 74 ).…”

Section: Deregulation Of Cholesterol Metabolism In Cancermentioning

confidence: 99%

The Lipid Metabolic Landscape of Cancers and New Therapeutic Perspectives

et al. 2020

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Lipid metabolism reprograming, as a hallmark of malignancy, has received renewed interest in recent years in such areas as energy sources, cell membrane components, and signaling molecules involved in the rapid tumor growth and the adaptation to the tumor microenvironment. Lipid metabolism deregulation in cancer involves multiple aspects, including an increased lipid uptake, endogenous de novo fatty acid synthesis, fatty acid oxidation, and cholesterol accumulation, thereby promoting tumor growth and progression. Recent advances in the understanding of specific metabolic alterations in cancer reveal novel pathogenesis mechanisms and a growing number of drugs targeting lipid metabolism have been applied in anti-tumor therapy. Thus, this review discusses the lipid metabolic landscape of cancers and the interplay with oncogenic signaling, and summarizes potential therapeutic targets to improve the therapeutic efficiency in cancer patients, in order to provide more reference and thinking for the treatment of lipid metabolism of cancer patients.

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Clinical relevance of cholesterol homeostasis genes in colorectal cancer

Cited by 39 publications

References 33 publications

Modulation of LXR signaling altered the dynamic activity of human colon adenocarcinoma cancer stem cells in vitro

Modulation of LXR signaling altered the dynamic activity of human colon adenocarcinoma cancer stem cells in vitro

Alterations of Lipid Metabolism in Cancer: Implications in Prognosis and Treatment

The Lipid Metabolic Landscape of Cancers and New Therapeutic Perspectives

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