bims-meluca 2022-10-02 papers

Cancer Res. 2022 Sep 26. pii: CAN-22-1039. [Epub ahead of print]

Transient Systemic Autophagy Inhibition is Selectively and Irreversibly Deleterious to Lung Cancer.

Khoosheh Khayati, Vrushank Bhatt, Taijin Lan, Fawzi Alogaili, Wenping Wang, Enrique Lopez, Zhixian Sherrie Hu, Samantha Gokhale, Liam Cassidy, Masashi Narita, Ping Xie, Eileen White, Jessie Yanxiang Guo.

Autophagy is a conserved catabolic process that maintains cellular homeostasis. Autophagy supports lung tumorigenesis and is a potential therapeutic target in lung cancer. A better understanding of the importance of tumor cell-autonomous versus systemic autophagy in lung cancer could facilitate clinical translation of autophagy inhibition. Here, we exploited inducible expression of Atg5 shRNA to temporally control Atg5 levels and generate reversible tumor-specific and systemic autophagy loss mouse models of KrasG12D/+;p53-/- (KP) non-small cell lung cancer (NSCLC). Transient suppression of systemic but not tumor Atg5 expression significantly reduced established KP lung tumor growth without damaging normal tissues. In vivo 13C isotope tracing and metabolic flux analyses demonstrated that systemic Atg5 knockdown specifically led to reduced glucose and lactate uptake. As a result, carbon flux from glucose and lactate to major metabolic pathways, including the tricarboxylic acid cycle, glycolysis, and serine biosynthesis, was significantly reduced in KP NSCLC following systemic autophagy loss. Furthermore, systemic Atg5 knockdown increased tumor T cell infiltration, leading to T cell-mediated tumor killing. Importantly, intermittent transient systemic Atg5 knockdown, which resembles what would occur during autophagy inhibition for cancer therapy, significantly prolonged lifespan of KP lung tumor-bearing mice, resulting in recovery of normal tissues but not tumors. Thus, systemic autophagy supports the growth of established lung tumors by promoting immune evasion and sustaining cancer cell metabolism for energy production and biosynthesis, and the inability of tumors to recover from loss of autophagy provides further proof of concept that inhibition of autophagy is a valid approach to cancer therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-1039

Br J Clin Pharmacol. 2022 Sep 26.

Tumor, whole blood, plasma, and tissue concentrations of metformin in lung cancer patients.

Joseph D Phillips, Darcy B Pooler, Dylan B Ness, Kayla Fay, Steven Tau, Eugene Demidenko, Riley A Hampsch, Lionel D Lewis, Todd W Miller.

BACKGROUND AND PURPOSE: Metformin is used for the management of type 2 diabetes mellitus (T2DM). Metformin is being tested clinically as an anti-cancer agent. Metformin concentrations safely achievable in human solid tissues including tumors are unknown. Metformin concentration in tissue compartments as a function of dose will inform rational dosing in preclinical models and interpretation of clinical results.
EXPERIMENTAL APPROACH: Subjects with solid tumors to be treated by resection and either (A) willingness to take metformin for 7-10 days before surgery, or (B) taking metformin for T2DM were eligible. Whole blood, plasma, tumor, tumor-adjacent uninvolved tissue, and subcutaneous adipose tissue were obtained for LC-MS/MS to measure metformin concentrations.
KEY RESULTS: All subjects had primary lung tumors. Metformin dose was significantly correlated with drug concentrations in all tissues analyzed. Inter-subject metformin concentrations varied by over two orders of magnitude. Metformin concentrations were significantly higher in tumor tissues and lower in adipose tissues compared to other tissues. Concentrations in blood and plasma were significantly correlated with concentrations in solid tissues.
CONCLUSION AND IMPLICATIONS: Metformin accumulates in cellular compartments. Concentrations observed in plasma, blood, lung, and tumor tissues in subjects treated with doses FDA-approved for T2DM are lower than those typically used in tissue culture studies. However, such tissue concentrations are in line with those found within cultured cells treated with supra-pharmacological doses of metformin. Given the large inter-subject variability in metformin concentrations, it is imperative to determine whether there is an association between tissue metformin concentration and anti-cancer activity in humans.

Keywords: cancer; metformin; tissue distribution

DOI: https://doi.org/10.1111/bcp.15546

J Clin Lab Anal. 2022 Sep 26. e24714

Circular RNA hsa_circ_0018189 drives non-small cell lung cancer growth by sequestering miR-656-3p and enhancing xCT expression.

Jianfeng Cai, Yiping Zheng, Lie Dong, Xiangbin Zhang, Yinghui Huang.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the cancers with a high mortality rate. CircRNAs have emerged as an important regulatory factor in tumorigenesis in recent years. However, the detailed regulatory mechanism of a circular RNA cullin 2 (hsa_circ_0018189; hsa_circ_0018189) is still unclear in NSCLC.
METHODS: RNA levels of hsa_circ_0018189, microRNA (miR)-656-3p, and Solute carrier family seven member 11 (SLC7A11, xCT) were analyzed by real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR), and protein level was assessed by Western blot and immunohistochemical assay. Enzyme-linked immunosorbent assay was conducted to detect cell glutamine metabolism. Effects of hsa_circ_0018189 on cell proliferation, apoptosis, migration, and invasion were analyzed by corresponding assays. Luciferase reporter assay and RNA-immunoprecipitation assay confirmed the target relationship between miR-656-3p and hsa_circ_0018189 or xCT. The in vivo function of hsa_circ_0018189 was verified by xenograft mouse models.
RESULTS: Hsa_circ_0018189 abundance was overexpressed in NSCLC cells and samples. Deficiency of hsa_circ_0018189 lowered NSCLC cell proliferative, migrating, invading, and glutamine metabolism capacities, and hsa_circ_0018189 silencing inhibited the growth of tumors in vivo. Hsa_circ_0018189 could up-regulate xCT by sponging miR-656-3p. And miR-656-3p downregulation or xCT overexpression partly overturned hsa_circ_0018189 knockdown or miR-656-3p mimic-mediated repression of NSCLC cell malignancy.
CONCLUSION: Hsa_circ_0018189 drove NSCLC growth by interacting with miR-656-3p and upregulating xCT.

Keywords: Hsa_circ_0018189; NSCLC; miR-656-3p; xCT

DOI: https://doi.org/10.1002/jcla.24714