bims-glucam 2021-08-22 papers

Cancer Manag Res. 2021 ;13 6291-6307

The Crucial Roles of Intermediate Metabolites in Cancer.

Metabolic alteration, one of the hallmarks of cancer cells, is important for cancer initiation and development. To support their rapid growth, cancer cells alter their metabolism so as to obtain the necessary energy and building blocks for biosynthetic pathways, as well as to adjust their redox balance. Once thought to be merely byproducts of metabolic pathways, intermediate metabolites are now known to mediate epigenetic modifications and protein post-transcriptional modifications (PTM), as well as connect cellular metabolism with signal transduction. Consequently, they can affect a myriad of processes, including proliferation, apoptosis, and immunity. In this review, we summarize multiple representative metabolites involved in glycolysis, the pentose phosphate pathway (PPP), the tricarboxylic acid (TCA) cycle, lipid synthesis, ketogenesis, methionine metabolism, glutamine metabolism, and tryptophan metabolism, focusing on their roles in chromatin and protein modifications and as signal-transducing messengers.

Keywords: epigenetic modification; extra-metabolic functions; oncometabolites; post-transcriptional modifications; signaling transduction

DOI: https://doi.org/10.2147/CMAR.S321433

Kaohsiung J Med Sci. 2021 Aug 18.

Silencing of circ_0000517 suppresses proliferation, glycolysis, and glutamine decomposition of non-small cell lung cancer by modulating miR-330-5p/YY1 signal pathway.

Zhong-Xing Bing, Jia-Qi Zhang, Gui-Ge Wang, Yan-Qing Wang, Tian-Ge Wang, Dan-Qing Li.

In recent years, circular RNA (circRNA) has been found to be involved in a variety of cancer processes. More and more attention has been paid to the research of circRNA in lung cancer. This study aims to investigate whether circ_0000517 affected the physiology of non-small cell lung cancer (NSCLC) and the underlying mechanism. The results demonstrated that circ_0000517 was highly expressed in lung cancer tissues and cells, and overexpression of circ_0000517 was negatively correlated with the prognosis of NSCLC patients. Silencing of circ_0000517 significantly inhibited the proliferation, glycolysis, and glutamine decomposition of NSCLC cells in vitro and repressed the growth of xenografted tumors in vivo. Moreover, knockdown of circ_0000517 attenuated the expression of PCNA, HK2, LDHA, ASCT2, and GLS1. Further study found that circ_0000517 targeted miR-330-5p and miR-330-5p targeted YY1. In addition, miR-330-5p inhibitor reversed inhibition of cancer cell proliferation, glycolysis, and glutamine decomposition induced by si-circ_0000517. In conclusion, our study revealed that silencing of circ_0000517 improved the progression of NSCLC through regulating miR-330-5p/YY1 axis.

Keywords: NSCLC; YY1; circ_0000517; glycolysis; miR-330-5p

DOI: https://doi.org/10.1002/kjm2.12440

Clin Cancer Res. 2021 Aug 18. pii: clincanres.4789.2020. [Epub ahead of print]

Recurrent human papillomavirus-related head and neck cancer undergoes metabolic re-programming and is driven by oxidative phosphorylation.

Avani Vyas, Richard A Harbison, Daniel L Faden, Mark Kubik, Drake Palmer, Qing Zhang, Hatice U Osmanbeyoglu, Umamaheswar Duvvuri, Eduardo Méndez.

PURPOSE: Human papillomavirus (HPV) infection drives the development of some head and neck cancer squamous cell carcinomas (HNSCC). This disease is rapidly increasing in incidence worldwide. Although these tumors are sensitive to treatment, ~10% of patients fail therapy. However, the mechanisms that underlie treatment failure remain unclear.
EXPERIMENTAL DESIGN: We performed RNA seq on tissues from matched primary (pOPSCC) and metachronous recurrent cancers (rOPSCC) to identify transcriptional differences to gain mechanistic insight into the evolutionary adaptations of metachronous recurrent tumors. We used HPV-related HNSCC cells lines to investigate the effect of (1) NRF2 overexpression on growth in vitro and in vivo (2) OXPHOS inhibition using IACS-010759 on NRF2 dependent cells (3) combination of cisplatin and OXPHOS inhibition.
RESULTS: The oxidative phosphorylation (OXPHOS) pathway is enriched in recurrent HPV-associated HNSCC and may contribute to treatment failure. NRF2-enriched HNSCC samples from the Cancer Genome Atlas with enrichment in OXPHOS, fatty acid metabolism, Myc, Mtor, ROS, and glycolytic signaling networks exhibited worse survival. HPV-positive HNSCC cells demonstrated sensitivity to the OXPHOS inhibitor, in a NRF2-dependent manner. Further, using murine xenograft models, we identified NRF2 as a driver of tumor growth. Mechanistically, NRF2 drives ROS and mitochondrial respiration, and NRF2 is a critical regulator of redox homeostasis that can be crippled by disruption of OXPHOS. NRF2 also mediated cisplatin sensitivity in endogenously overexpressing primary HPV-related HNSCC cells.
CONCLUSIONS: These results unveil a paradigm shifting translational target harnessing NRF2-mediated metabolic reprogramming in HPV-related HNSCC.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-4789

Pharmacol Ther. 2021 Aug 11. pii: S0163-7258(21)00166-2. [Epub ahead of print] 107964

Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics.

Yoshikatsu Kanai.

Cancer cells require a massive supply of nutrients, including sugars and amino acids-the upregulation of transporters for each nutrient contributes to meet the demand. Distinct from glucose transporters, amino acid transporters include ones whose expression is specific to cancer cells. For example, LAT1 (SLC7A5) displays protein expression mostly limited to the plasma membrane of cancer cells. The exceptions are the placental barrier and the blood-brain barrier, where immunohistochemical and mass spectrometric studies have shown LAT1 expression, although their levels are supposed to be lower than those in cancers. The expression of LAT1 has been reported in cancers from various tissue origins, where high LAT1 expression is related to the poor prognosis of patients. LAT1 is essential for cancer cell growth because the pharmacologic inhibition and knockdown/knockout of LAT1 suppress the proliferation of cancer cells and the growth of xenograft tumors. The inhibition of LAT1 suppresses protein synthesis by downregulating the mTORC1 signaling pathway and mobilizing the general amino acid control (GAAC) pathway in cancer cells. LAT1 is, thus, a candidate molecular target for the diagnosis and therapeutics of cancers. 18F-labeled 3-fluoro-l-α-methyl-tyrosine (FAMT) is used as a LAT1-specific PET probe for cancer detection due to the LAT1 specificity of α-methyl aromatic amino acids. FAMT accumulation is cancer-specific and avoids non-cancer lesions, including inflammation, confirming the cancer-specific expression of LAT1 in humans. Due to the cancer-specific nature, LAT1 can also be used for cancer-specific delivery of anti-tumor agents such as l-para-boronophenylalanine used for boron neutron capture therapy and α-emitting nuclide-labeled LAT1 substrates developed for nuclear medicine treatment. Based on the importance of LAT1 in cancer progression, high-affinity LAT1-specific inhibitors have been developed for anti-tumor drugs. JPH203 (KYT0353) is such a compound designed based on the structure-activity relationship of LAT1 ligands. It is one of the highest-affinity inhibitors with less affecting other transporters. It suppresses tumor growth in vivo without significant toxicity in preclinical studies at doses enough to suppress tumor growth. In the phase-I clinical trial, JPH203 appeared to provide promising activity. Because the mechanisms of action of LAT1 inhibitors are novel, with or without combination with other anti-tumor drugs, they could contribute to the treatment of cancers that do not respond to current therapy. The LAT1-specific PET probe could also be used as companion diagnostics of the LAT1-targeting therapies to select patients to whom therapeutic benefits could be expected. Recently, the cryo-EM structure of LAT1 has been solved, which would facilitate the understanding of the mechanisms of the dynamic interaction of ligands and the binding site, and further designing new compounds with higher activity.

DOI: https://doi.org/10.1016/j.pharmthera.2021.107964

Biochem Pharmacol. 2021 Aug 16. pii: S0006-2952(21)00352-X. [Epub ahead of print] 114736

PIKE-A promotes glioblastoma growth by driving PPP flux through increasing G6PD expression mediated by phosphorylation of STAT3.

Mingming Sun, Hao Sheng, Tingfeng Wu, Jiaqi Song, Huanran Sun, Yingzhi Wang, Jiyan Wang, Zhen Li, Huifang Zhao, Junzhen Tan, Yanping Li, Guo Chen, Qingrong Huang, Yuan Zhang, Bei Lan, Shuangping Liu, Changliang Shan, Shuai Zhang.

Reprogramming of energy metabolism is a hallmarkofcancer, and the pentose phosphate pathway (PPP) is a major glucose metabolic pathway important for meeting the cellular demands of biosynthesis and anti-oxidant defense. Our previous study showed that phosphoinositide 3-kinase enhancer-activating Akt (PIKE-A) plays an important role in glioblastoma cell survival and growth under cellular energy stress condition. However, the crucial functions of PIKE-A in cancer energy metabolism are poorly understood.In the present study, we show that PIKE-A promotes DNA biosynthesis, NADPH production and inhibits reactive oxygen species (ROS) production, leading to increasing proliferation and growth of glioblastoma cell and suppressing cellular senescence. Mechanistically, PIKE-A binds to STAT3 and stimulates its phosphorylation mediated by tyrosine kinase Fyn, which enhances transcription of the rate-limitting enzyme glucose-6-phosphate dehydrogenase (G6PD) in the PPP. Finally, targeting PIKE-A-G6PD axis sensitizes glioblastoma to temozolomide (TMZ)treatment. This study reveals that STAT3 is a novel binding partner of PIKE-A which recruits Fyn to phosphorylate STAT3, contributing to the expression of G6PD, leading to promoting tumor growth and suppressing cellular senescence. Thus, the PIKE-A/STAT3/G6PD axis strongly links the PPP to carcinogenesis and may become a promising cancer therapeutic target.

Keywords: Fyn; G6PD; PIKE-A; STAT3; glioblastoma; phosphorylation

DOI: https://doi.org/10.1016/j.bcp.2021.114736

Naunyn Schmiedebergs Arch Pharmacol. 2021 Aug 20.

Combinatorial antitumor effects of amino acids and epigenetic modulations in hepatocellular carcinoma cell lines.

Yasmine A Hassan, Maged W Helmy, Asser I Ghoneim.

Hepatocellular carcinoma (HCC) is a highly fatal form of liver cancer. Recently, the interest in using amino acids as therapeutic agents has noticeably grown. The present work aimed to evaluate the possible antiproliferative effects of selected amino acids supplementation or deprivation in human HCC cell lines and to investigate their effects on critical signaling molecules in HCC pathogenesis and the outcomes of their combination with the histone deacetylase inhibitor vorinostat. HepG2 and Huh7 cells were treated with different concentrations of L-leucine, L-glutamine, or L-methionine and cell viability was determined using MTT assay. Insulin-like growth factor 1 (IGF1), phosphorylated ribosomal protein S6 kinase (p70 S6K), p53, and cyclin D1 (CD1) protein levels were assayed using ELISA. Caspase-3 activity was assessed colorimetrically. L-leucine supplementation (0.8-102.4 mM) and L-glutamine supplementation (4-128 mM) showed dose-dependent antiproliferative effects in both cell lines but L-methionine supplementation (0.2-25.6 mM) only affected the viability of HepG2 cells. Glutamine or methionine deprivation suppressed the proliferation of HepG2 cells whereas leucine deprivation had no effect on cell viability in both cell lines. The combination between the effective antiproliferative changes in L-leucine, L-glutamine, and L-methionine concentrations greatly suppressed cell viability and increased the sensitivity to vorinostat in both cell lines. The growth inhibitory effects were paralleled with significant decreases in IGF-1, phospho p70 S6k, and CD1 levels and significant elevations in p53 and caspase-3 activity. Changes in amino acids concentrations could profoundly affect growth in HCC cell lines and their response to epigenetic therapy.

Keywords: Glutamine; HepG2; Huh7; Leucine; Methionine; Vorinostat

DOI: https://doi.org/10.1007/s00210-021-02140-z