RSK2-inactivating mutations potentiate MAPK signaling and support cholesterol metabolism in hepatocellular carcinoma

Chan, Lo Kong; Ho, Danny; Kam, Charles Shing; Chiu, Elley Yung Tuen; Lo, Irene; Yau, Derek; Cheung, Elaine Tin Yan; Tang, Chung Ngai; Tang, Victor Wai Lun; Lee, Terence; Wong, Carmen Chak‐Lui; Chok, Kenneth S. H.; Chan, Albert C. Y.; Cheung, Tan To; Wong, Chun Ming

doi:10.1016/j.jhep.2020.08.036

Cited by 36 publications

(33 citation statements)

References 35 publications

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“…In TS cells, all activated pathways are related to cholesterol biosynthesis ( Figure 2 C). This result is in line with the finding that cholesterol biosynthesis is essential for tumorigenesis, cancer stemness, cancer metastasis, and 3D culture of cancer stem cells [ 33 , 34 , 35 , 36 , 37 ], but more research into the role of cholesterol biosynthesis in lung TS cells is needed. Through upstream analysis, we found that SMARCA4 and PAF1 are commonly activated upstream regulators in both drug-resistant cells and TS cells ( Figure 1 C and Figure 2 C).…”

Section: Discussionsupporting

confidence: 81%

SEZ6L2 Is an Important Regulator of Drug-Resistant Cells and Tumor Spheroid Cells in Lung Adenocarcinoma

et al. 2020

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Many lung cancer deaths result from relapses in distant organs, such as the brain or bones, after standard chemotherapy. For cancer cells to spread to other organs, they must survive as circulating tumor cells (CTCs) in blood vessels. Thus, reducing distant recurrence after chemotherapy requires simultaneously inhibiting drug resistance and CTC survival. Here, we investigated the molecular pathways and genes that are commonly altered in drug-resistant lung cancer cells and lung tumor spheroid (TS) cells. First, RNA sequencing was performed in drug-resistant cells and TS cells originating from H460 and A549 lung cancer cells. Bioinformatic pathway analysis showed that cell cycle-related pathways were downregulated in drug-resistant cells, and cholesterol biosynthesis-related pathways were upregulated in TS cells. Seizure-related 6 homolog-like 2 (SEZ6L2) was selected as a gene that was commonly upregulated in both drug-resistant cells and TS cells, and that showed elevated expression in samples from lung adenocarcinoma patients. Second, the protein expression of SEZ6L2 was analyzed by flow cytometry. The proportions of SEZ6L2 positive cells among both drug-resistant cells and TS cells was increased. Finally, as SEZ6L2 is a transmembrane protein with an extracellular region, the function of SEZ6L2 was disrupted by treatment with an anti-SEZ6L2 antibody. Treatment with the anti-SEZ6L2 antibody reduced drug resistance and TS formation. Overall, our data showed that SEZ6L2 plays an important role in drug resistance and TS formation and may be a therapeutic target for reducing distant recurrence of lung adenocarcinoma.

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Section: Discussionsupporting

confidence: 81%

SEZ6L2 Is an Important Regulator of Drug-Resistant Cells and Tumor Spheroid Cells in Lung Adenocarcinoma

et al. 2020

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“…Thus, cholesterol import, its biosynthesis, and its export all are modulated in cancer cells. Multiple mechanisms promote deregulation of cholesterol homeostasis and lead to cancer development ( Smith and Land, 2012 ; Yun et al, 2014 ; Vassilev et al, 2015 ; Jun et al, 2020 ; Chan et al, 2021 ). The transcriptional controller of cholesterol biosynthesis SREBP-1 and 2 are elevated in various cancers ( Li et al, 2016 ; Jie et al, 2019 ; Sharma et al, 2019 ).…”

Section: Cholesterol In Cancer Cellsmentioning

confidence: 99%

Cholesterol-Lowering Drugs on Akt Signaling for Prevention of Tumorigenesis

Kumar

Mandal

2021

Front. Genet.

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Cholesterol has been reported to be accumulated in cancer cells. The metabolic dysregulation of the cholesterol is associated with tumor development and progression. The cholesterol-lowering drugs have been found to be involved in the prevention and treatment of various cancers. Akt, a serine/threonine kinase, can modulate the role of several downstream proteins involved in cell proliferation, migration, invasion, metabolism, and apoptosis. Since its involvement in several signaling pathways, its dysregulation is commonly reported in several cancers. Thus, targeting Akt could be an effective approach for cancer prevention and therapy. Cholesterol-lowering drugs have been found to affect the expression of Akt, and its activation in the cancer cells and thus have shown anticancer activity in different type of cancers. These drugs act on various signaling pathways such as PTEN/Akt, PI3k/Akt, Akt/NF-κB, Akt/FOXO1, Akt/mTOR, etc., which will be discussed in this article. This review article will discuss the significance of cholesterol in cancer cells, cholesterol-lowering drugs, the role of Akt in cancer cells, and the effects of cholesterol-lowering drugs on Akt in the prevention of therapy resistance and metastasis.

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“…The signaling pathway of MAPKs, a highly conserved signal transduction pathway, is involved in regulating diverse cellular and physiological processes, for example, cell growth, apoptosis, in ammation, proliferation, differentiation, and migration [30,31]. Aberrant regulation of the MAPK signaling pathway also has been associated with various cancers, for example, hepatocellular carcinoma [32], breast cancer [33], and gastric cancer [34] and so on. In addition, research reported that angelicin regulates LPS-induced in ammation by suppressing MAPK pathways [35].…”

Section: Discussionmentioning

confidence: 99%

Angelicin Shows Antitumor Effects On The Oral Squamous Cell Carcinoma By Negatively Regulating DUSP6-Mediated cMYC-MAPK Signaling Pathway

Liu¹,

Shang²,

Qi³

et al. 2021

Preprint

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Background: Angelicin has been reported to have antitumor effects on many cancers. However, few studies on angelicin in oral squamous cell carcinoma (OSCC) have been performed. Methods: In this study, we performed a cell cycle and apoptosis assay, wound healing assay, and transwell assay to assess the effects of angelicin on malignant phenotypes of OSCC in vitro. To determine the potential regulatory mechanism, we conducted differentially expressed genes analysis of OSCC cells. Subsequently, nude mouse xenograft models were used to evaluate the function of angelicin and validate the regulatory mechanism in vivo. Results: The results showed that angelicin inhibited the malignant phenotype of OSCC in vitro and reduced tumor formation in vivo. Mechanistically, angelicin induced the downregulation of the significantly different gene—dual-specificity phosphatase 6 (DUSP6) and the downstream transcription factor c-MYC in the mitogen-activated protein kinase (MAPK) signaling pathway. Conclusion: Our results indicate that angelicin has antitumor effects on OSCC by negatively regulating the DUSP6-mediated cMYC-MAPK signaling pathway and is a promising antitumor drug in OSCC therapy.

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RSK2-inactivating mutations potentiate MAPK signaling and support cholesterol metabolism in hepatocellular carcinoma

Cited by 36 publications

References 35 publications

SEZ6L2 Is an Important Regulator of Drug-Resistant Cells and Tumor Spheroid Cells in Lung Adenocarcinoma

SEZ6L2 Is an Important Regulator of Drug-Resistant Cells and Tumor Spheroid Cells in Lung Adenocarcinoma

Cholesterol-Lowering Drugs on Akt Signaling for Prevention of Tumorigenesis

Angelicin Shows Antitumor Effects On The Oral Squamous Cell Carcinoma By Negatively Regulating DUSP6-Mediated cMYC-MAPK Signaling Pathway

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