bims-meluca 2019-07-14 papers

Cell Rep. 2019 Jul 09. pii: S2211-1247(19)30792-2. [Epub ahead of print]28(2): 512-525.e6

Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors.

Drug resistance is a significant hindrance to effective cancer treatment. Although resistance mechanisms of epidermal growth factor receptor (EGFR) mutant cancer cells to lethal EGFR tyrosine kinase inhibitors (TKI) treatment have been investigated intensively, how cancer cells orchestrate adaptive response under sublethal drug challenge remains largely unknown. Here, we find that 2-h sublethal TKI treatment elicits a transient drug-tolerant state in EGFR mutant lung cancer cells. Continuous sublethal treatment reinforces this tolerance and eventually establishes long-term TKI resistance. This adaptive process involves H3K9 demethylation-mediated upregulation of branched-chain amino acid aminotransferase 1 (BCAT1) and subsequent metabolic reprogramming, which promotes TKI resistance through attenuating reactive oxygen species (ROS) accumulation. Combination treatment with TKI- and ROS-inducing reagents overcomes this drug resistance in preclinical mouse models. Clinical information analyses support the correlation of BCAT1 expression with the EGFR TKI response. Our findings reveal the importance of BCAT1-engaged metabolism reprogramming in TKI resistance in lung cancer.

Keywords: BCAT1; EGFR tyrosine kinase inhibitors; branched-chain amino acids; drug resistance; lung cancer; metabolic reprogramming

DOI: https://doi.org/10.1016/j.celrep.2019.06.026

Proteomics. 2019 Jul 12. e1800486

Inhibition of anaplerotic glutaminolysis underlies selenite toxicity in human lung cancer.

Ronald C Bruntz, Alex C Belshoff, Yan Zhang, Jessica K A Macedo, Richard M Higashi, Andrew N Lane, Teresa W-M Fan.

Large clinical trials and studies in model systems suggest that the chemical form of selenium may dictate chemopreventive and chemotherapeutic efficacy. Selenite induces excess ROS production, which mediates autophagy and eventual cell death in non-small cell lung cancer (NSCLC) adenocarcinoma A549 cells. The exact mechanisms that underlie these phenotypic effects are unclear, thus the clinical relevance of selenite or other selenocompounds for cancer therapy remains to be determined. Using stable isotope-resolved metabolomics (SIRM) and gene expression analysis, we previously showed that selenite simultaneously disrupts glycolysis, the Krebs cycle, and polyamine metabolism in A549 cells, potentially through perturbed glutaminolysis. Glutaminolysis is a vital anaplerotic process for the proliferation and survival of many cancer cells. Here we investigated the role of key glutaminolytic enzyme glutaminase 1 (GLS1) in selenite's toxicity in A549 cells and in patient-derived lung cancer tissue slices. Using [13 C6 ]-glucose and [13 C5 ,15 N2 ]-glutamine as tracers, we tracked the time course of selenite's action on multiple pathways. We found that selenite inhibited glutaminolysis and glutathione synthesis by suppressing GLS1 expression in addition to blocking the Krebs cycle but transiently activating the pyruvate carboxylase activity. Glutamate supplementation in part rescued these anti-proliferative and oxidative stress activities. Similar metabolic perturbations and tissue necrosis were evident in human patients' cancerous lung tissues in ex vivo experiments with selenite. Altogether, our results support the hypothesis that GLS1 suppression mediates part of the anti-cancer activity of selenite both in vitro and ex vivo. This article is protected by copyright. All rights reserved.

Keywords: [13C5,15N2]-glutamine; [13C6]-glucose; glutaminolysis; lung cancer; selenite; stable isotope resolved metabolomics

DOI: https://doi.org/10.1002/pmic.201800486

Cell Death Dis. 2019 Jul 08. 10(7): 525

4-hydroxyphenylpyruvate dioxygenase promotes lung cancer growth via pentose phosphate pathway (PPP) flux mediated by LKB1-AMPK/HDAC10/G6PD axis.

Changliang Shan, Zhaoliang Lu, Zhen Li, Hao Sheng, Jun Fan, Qi Qi, Shuangping Liu, Shuai Zhang.

4-hydroxyphenylpyruvate dioxygenase (HPD) is an important modifier of tyrosine metabolism. However, the precise contribution of HPD to cancer metabolism and tumorigenesis remains unclear. In this study, we found that HPD was highly expressed in lung cancer and its higher expression correlated with poor prognosis in lung cancer patients. Suppressed HPD expression was sufficient to decrease oxidative pentose phosphate pathway (PPP) flux, leading to reduced RNA biosynthesis and enhanced reactive oxygen species (ROS) level, attenuated cancer cell proliferation, and tumor growth. Mechanistically, HPD not only promotes tyrosine catabolism leading to increased acetyl-CoA levels, the source of histone acetylation, but also stimulates histone deacetylase 10 (HDAC10) translocation from the nucleus into the cytoplasm mediated by tumor suppressor liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) signaling. Both controlled histone acetylation modification, which enhanced transcription of the important PPP enzyme Glucose-6-Phosphate Dehydrogenase (G6PD). Thus, this study reveals HPD as a novel regulator of LKB1-AMPK signaling-mediated HDAC10 nuclear location, which contributes to G6PD expression in promoting tumor growth, which is a promising target for lung cancer treatment.

DOI: https://doi.org/10.1038/s41419-019-1756-1

Phytomedicine. 2019 Jun 27. pii: S0944-7113(19)30167-9. [Epub ahead of print]63 153000

Nootkatone, an AMPK activator derived from grapefruit, inhibits KRAS downstream pathway and sensitizes non-small-cell lung cancer A549 cells to adriamycin.

Le Van Manh Hung, Jeong Yong Moon, Ji-Yeon Ryu, Somi Kim Cho.

BACKGROUND: Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and it is intrinsically resistant to anticancer drugs. Nootkatone (NKT), which is the main fragrant component of grapefruit, has been identified as a bioactive compound with a wide range of beneficial applications. NKT can activate AMP-activated protein kinase (AMPK) in liver and muscle cells, however, little is known about the role of NKT in cancer, particularly its role in NSCLC with high rates of liver kinase B1 (LKB1) and KRAS mutations.
PURPOSE: The anti-cancer activities of NKT in NSCLC A549 cells and ADR-resistant A549/ADR cells were investigated and compared to those of metformin, an AMPK activator that is used clinically as an AMPK activator.
METHODS: Cell viability, proliferation and NKT sensitization were determined by the MTT assay. Mechanisms of NKT against anti-cancer activities including AMPK activation, cell cycle arrest, and synergistic cytotoxic effect were evaluated by Western blot analysis, and flow cytometry. In in vivo experiments, athymic BALB/c male nude mice were used for experiments. After the successful generation of tumor models through subcutaneous injection of A549/ADR cells, NKT and/or ADR were administered and mice were kept for weekly measurements for up to 7 weeks. The animals were then sacrificed, and the tumors were removed from all animals and weighed.
RESULTS: NKT activated AMPK via LKB1-independent and CAMKK2-dependent pathways, leading to inhibition of cell growth and induction of G1 cell arrest. The effect of NKT is comparable but superior to that of metformin, an AMPK activator in clinical use. Importantly, NKT inhibited the activation of oncogenic AKT and ERK proteins, while metformin inhibited AKT but failed to impact ERK, the major oncogenic protein of NSCLC cells with KRAS mutation. The synergistic activity of NKT and ADR was more effective than that of metformin and ADR. In vivo data confirmed synergistic effects of NKT and ADR without systemic side effects.
CONCLUSION: We demonstrate for the first time that NKT can sensitize ADR-resistant A549/ADR cells to ADR in vitro and in vivo. Metformin, on the other hand, failed to show any synergistic effect with ADR in A549/ADR cells.

Keywords: AMPK; Adriamycin; Metformin; Non-small-cell lung cancer; Nootkatone; Synergistic effect

DOI: https://doi.org/10.1016/j.phymed.2019.153000

Acta Pharmacol Sin. 2019 Jul 08.

Somatic and germline mutations in the tumor suppressor gene PARK2 impair PINK1/Parkin-mediated mitophagy in lung cancer cells.

Zeng-Li Zhang, Na-Na Wang, Qi-Lian Ma, Yang Chen, Li Yao, Li Zhang, Qiu-Shi Li, Min-Hua Shi, Hong-Feng Wang, Zheng Ying.

PARK2, which encodes Parkin, is a disease-causing gene for both neurodegenerative disorders and cancer. Parkin can function as a neuroprotector that plays a crucial role in the regulation of mitophagy, and germline mutations in PARK2 are associated with Parkinson's disease (PD). Intriguingly, recent studies suggest that Parkin can also function as a tumor suppressor and that somatic and germline mutations in PARK2 are associated with various human cancers, including lung cancer. However, it is presently unknown how the tumor suppressor activity of Parkin is affected by these mutations and whether it is associated with mitophagy. Herein, we show that wild-type (WT) Parkin can rapidly translocate onto mitochondria following mitochondrial damage and that Parkin promotes mitophagic clearance of mitochondria in lung cancer cells. However, lung cancer-linked mutations inhibit the mitochondrial translocation and ubiquitin-associated activity of Parkin. Among all lung cancer-linked mutants that we tested, A46T Parkin failed to translocate onto mitochondria and could not recruit downstream mitophagic regulators, including optineurin (OPTN) and TFEB, whereas N254S and R275W Parkin displayed slower mitochondrial translocation than WT Parkin. Moreover, we found that deferiprone (DFP), an iron chelator that can induce mitophagy, greatly increased the death of A46T Parkin-expressing lung cancer cells. Taken together, our results reveal a novel mitophagic mechanism in lung cancer, suggesting that lung cancer-linked mutations in PARK2 are associated with impaired mitophagy and identifying DFP as a novel therapeutic agent for PARK2-linked lung cancer and possibly other types of cancers driven by mitophagic dysregulation.

Keywords: Parkin; autophagy; cancer; mitophagy; ubiquitin

DOI: https://doi.org/10.1038/s41401-019-0260-6