bims-meluca 2020-06-07 papers

Cancers (Basel). 2020 May 28. pii: E1382. [Epub ahead of print]12(6):

The Combination of Loss of ALDH1L1 Function and Phenformin Treatment Decreases Tumor Growth in KRAS-Driven Lung Cancer.

Seon-Hyeong Lee, Yoon Jeon, Joon Hee Kang, Hyonchol Jang, Ho Lee, Soo-Youl Kim.

Lung adenocarcinoma cells express high levels of ALDH1L1, an enzyme of the one-carbon pathway that catalyzes the conversion of 10-formyltetrahydrofolate into tetrahydrofolate and NAD(P)H. In this study, we evaluated the potential of ALDH1L1 as a therapeutic target by deleting the Aldh1l1 gene in KrasLA2 mice, a model of spontaneous non-small cell lung cancer (NSCLC). Reporter assays revealed KRAS-mediated upregulation of the ALDH1L1 promoter in human NSCLC cells. Aldh1l1-/- mice exhibited a normal phenotype, with a 10% decrease in Kras-driven lung tumorigenesis. By contrast, the inhibition of oxidative phosphorylation inhibition using phenformin in Aldh1l1-/-; KrasLA2 mice dramatically decreased the number of tumor nodules and tumor area by up to 50%. Furthermore, combined treatment with pan-ALDH inhibitor and phenformin showed a decreased number and area of lung tumors by 70% in the KrasLA2 lung cancer model. Consistent with this, previous work showed that the combination of ALDH1L1 knockdown and phenformin treatment decreased ATP production by as much as 70% in NSCLS cell lines. Taken together, these results suggest that the combined inhibition of ALDH activity and oxidative phosphorylation represents a promising therapeutic strategy for NSCLC.

Keywords: KRAS; NSCLC; aldehyde dehydrogenase 1L1; cancer metabolism

DOI: https://doi.org/10.3390/cancers12061382

J Cancer. 2020 ;11(15): 4442-4452

High expression of PKM2 synergizes with PD-L1 in tumor cells and immune cells to predict worse survival in human lung adenocarcinoma.

Long Long, Mengxi Chen, Yu Yuan, Alex Lau Ming, Wei Guo, Kaisong Wu, Honglei Chen.

Background: Immunotherapy targeting PD-1/PD-L1 represents a breakthrough in the treatment of lung cancer. Pyruvate kinase M2 (PKM2) is not only a critical player in glycolysis, but also conducive to tumor progression and immune response. While both have been linked to lung adenocarcinoma (AC), the correlation and clinical significance of PKM2 and PD-L1 expression in human lung AC tissues remains not entirely explored. Methods: Expression of PKM2 and PD-L1 proteins were detected by immunohistochemistry in 74 lung AC cases and the corresponding noncancerous tissues. Simultaneously, multiplex immunofluorescence was used to detect PKM2, PD-L1, CK, CD3, and CD68 in the lung AC tissues. We measured expression patterns and co-localization of these markers, evaluating their association with clinicopathological features and overall survival. Validation of findings was conducted using mRNA expression data from The Cancer Genome Atlas (TCGA) of 515 lung AC cases. Results: High expression of PKM2 in tumor cells was significantly related with lymph node metastasis and TNM stage (p=0.035, p=0.017, respectively). Moreover, PKM2 expression in tumor cells was positively correlated with tumor PD-L1 expression. High expression of PKM2, PD-L1 in tumor cells and immune cells predicted high mortality rate and poorer survival rates, respectively. Additionally, multivariate Cox regression models indicated that high expression of PKM2 in tumor cells was an independent prognostic factor. Based on TCGA genomic data, high PKM2 mRNA expression was significantly associated with poorer survival (p=0.001). Conclusion: High expression of PKM2 synergizes with PD-L1 in tumor cells and immune cells to predict poorer survival rates in patients with lung AC.

Keywords: Energy metabolism; Immune checkpoint therapy; Lung adenocarcinoma; PD-L1; PKM2

DOI: https://doi.org/10.7150/jca.42610

Antioxid Redox Signal. 2020 May 30.

TARGETING HUMAN LUNG ADENOCARCINOMA WITH A SUPPRESSOR OF MITOCHONDRIAL SUPEROXIDE PRODUCTION.

Nivea Dias Amoedo, Laetitia Dard, Saharnaz Sarlak, Walid Mahfouf, Wendy Blanchard, Benoît Rousseau, Julien Izotte, Stephane Claverol, Didier Lacombe, Hamid Reza Rezvani, Ciro Leonardo Pierri, Rodrigue Rossignol.

AIMS: REDOX signaling from reactive oxygen species generated by the mitochondria (mtROS) has been implicated in cancer growth and survival. Here, we investigated the effect of AOL (5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione), a recently characterized member of the new class of mtROS suppressors (S1QELs), on human lung adenocarcinoma proteome reprogramming, bioenergetics and growth.
RESULTS: AOL reduced steady-state cellular ROS levels in human lung cancer cells without altering the catalytic activity of complex I. AOL treatment induced dose-dependent inhibition of lung cancer cell proliferation and triggered a reduction in tumor growth in vivo. Molecular investigations demonstrated that AOL reprogrammed the proteome of human lung cancer cells. In particular, AOL suppressed the determinants of the Warburg effect and reduced the expression of STAT3, a master regulator of lung carcinogenesis. Comparison of the molecular changes induced by AOL and MitoTEMPO, a mtROS scavenger that is not a S1QEL, identified a core component of 217 proteins commonly altered by the two treatments, as well as drug-specific targets.
INNOVATION: This study provides proof-of-concept data on the anticancer effect of AOL on mouse orthotopic human lung tumors. A unique dataset on proteomic reprogramming by AOL and MitoTEMPO is also provided. Last, our study revealed the repression of STAT3 by S1QEL AOL.
CONCLUSION: Our findings demonstrate the preclinical anticancer properties of S1QEL AOL and delineate its mode of action on REDOX and cancer signaling.

DOI: https://doi.org/10.1089/ars.2019.7892

Theranostics. 2020 ;10(13): 6048-6060

The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase.

Xinyuan Ding, Yuting Gu, Min Jin, Xin Guo, Sudong Xue, Caihong Tan, Jiefang Huang, Wanlin Yang, Mingxing Xue, Qianjun Zhou, Wenjuan Wang, Yanyun Zhang.

Rationale: Resistance to pemetrexed (PEM)-based chemotherapy is a major cause of progression in non-small cell lung cancer (NSCLC) patients. The deubiquitinating enzyme UCHL1 was recently found to play important roles in chemoresistance and tumor progression. However, the potential roles and mechanisms of UCHL1 in PEM resistance remain unclear. Methods: Bioinformatics analyses and immunohistochemistry were used to evaluate UCHL1 expression in NSCLC specimens. Kaplan-Meier analysis with the log-rank test was used for survival analyses. We established PEM-resistant NSCLC cell lines by exposing them to step-wise increases in PEM concentrations, and in vitro and in vivo assays were used to explore the roles and mechanisms of UCHL1 in PEM resistance using the NSCLC cells. Results: In chemoresistant tumors from NSCLC patients, UCHL1 was highly expressed and elevated UCHL1 expression was strongly associated with poor outcomes. Furthermore, UCHL1 expression was significantly upregulated in PEM-resistant NSCLC cells, while genetic silencing or inhibiting UCHL1 suppressed resistance to PEM and other drugs in NSCLC cells. Mechanistically, UCHL1 promoted PEM resistance in NSCLC by upregulating the expression of thymidylate synthase (TS), based on reduced TS expression after UCHL1 inhibition and re-emergence of PEM resistance upon TS restoration. Furthermore, UCHL1 upregulated TS expression, which mitigated PEM-induced DNA damage and cell cycle arrest in NSCLC cells, and also conferred resistance to PEM and other drugs. Conclusions: It appears that UCHL1 promotes PEM resistance by upregulating TS in NSCLC cells, which mitigated DNA damage and cell cycle arrest. Thus, UCHL1 may be a therapeutic target for overcoming PEM resistance in NSCLC patients.

Keywords: UCHL1; chemoresistance; non-small cell lung cancer; pemetrexed; thymidylate synthase

DOI: https://doi.org/10.7150/thno.42096

Nutr Cancer. 2020 Jun 01. 1-8

The Role of a Cachexia Grading System in Patients with Non-Small Cell Lung Cancer Treated with Immunotherapy: Implications for Survival.

Jenny G Turcott, Julio E Martinez-Samano, Andrés F Cardona, Suraj Samtani Bassarmal, Laura Alejandra Ramírez-Tirado, Zyanya Lucia Zatarain-Barrón, Feliciano Barrón, Luis Corrales, Claudio Martín, Pablo Alan Barragán-Castillo, Alejandro Ruiz-Patiño, Diana Flores-Estrada, Oscar Arrieta.

Objective: The association between cancer-induced weight-loss (CIWL) and poor clinical outcomes in patients treated with immunotherapy is scarcely understood. We evaluated the use of a cachexia-grading system in IO-treated non-small cell lung cancer (NSCLC) patients in order to predict clinical outcomes.Materials: 300 patients with NSCLC, who received immunotherapy during any line of therapy, were included. All patients were graded according to a previously validated cachexia scale, which takes into consideration body mass index (BMI) and weight loss, stratifying patients into five risk categories (0 [pre-cachexia] - 4 [refractory cachexia]). Primary endpoint was overall survival (OS).Results: Ninety-one (30.3%) patients were classified in the low risk category, 176 (58.6%) were classified in the intermediate risk category and 33 (11%) were in the high risk category. Patients classified as low-risk had a significantly longer OS compared with those with intermediate or high risk (22.4 mo, [95%CI: 16.6-NR] vs. 17.1 [95%CI: 13.5-22.4] vs. 8.0 [3.9-18.4]; p < 0.001). In the multivariate analysis, after adjusting for age, hemoglobin and ORR, hazard of death increased as per the cachexia risk scale (Hazard ratio: 1.62 [1.22-2.16]; p = 0.001).Conclusion: Cachexia is independently associated with worse OS in NSCLC patients who receive immunotherapy, highlighting the role for nutritional assessment.

DOI: https://doi.org/10.1080/01635581.2020.1769691