bims-meluca 2023-08-06 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–08–06
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

CDK12 loss inhibits cell proliferation by regulating TBK1 in non-small cell lung cancer cells.
Role of exosomes in transferring chemoresistance through modulation of cancer glycolytic cell metabolism.
Prediction of prognosis and immunotherapy response in lung adenocarcinoma based on CD79A, DKK1 and VEGFC.
Modulation of host glutamine anabolism enhances the sensitivity of small cell lung cancer to chemotherapy.
Predictive value of the prognostic nutritional index in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.
Lipid metabolism pathway genes and lung cancer: ACADSB rs12220683G>C is associated with better survival outcome in patients with non-small cell lung cancer.

Mol Cell Probes. 2023 Jul 29. pii: S0890-8508(23)00032-4. [Epub ahead of print]71 101923

CDK12 loss inhibits cell proliferation by regulating TBK1 in non-small cell lung cancer cells.

Xiaoli Liu, Yangdong Liu, Wenjun Chai, Mingxia Yan, Hui Li, Jing Li, Lei Sun, Yue Cao, Qian Liu, Yuexi Sun, Hongyu Pan.

  Lung cancer is one of the most common malignant tumors and has a poor prognosis and a low survival rate. Traditional treatments, such as radiotherapy and chemotherapy, still face some challenges because of high drug resistance and toxicity. Therefore, it is necessary to discover a new kind of targeted drug with low toxicity and high efficiency. CDK12 is a cell cycle-dependent kinase whose main function is to activate RNA polymerase II (RNAPII) and promote the transcriptional extension of RNA. However, the role and molecular mechanism of CDK12 in lung cancer are still unclear. In this study, the mutation and RNA-Seq data of CDK12 in lung adenocarcinoma and squamous cell carcinoma were downloaded from The Cancer Genome Atlas (TCGA) database and analyzed with the custom scripts. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) and cell colony formation assays. A subcutaneous tumor experiment in nude mice was used to examine the effects of CDK12 knockdown on the in vivo tumor growth of NSCLC cells. The cell cycle distribution and the apoptosis rate of lung cancer cells were assessed by flow cytometry. Regulation of TANK-binding kinase 1 (TBK1) by CDK12 was evaluated by quantitative PCR, immunoprecipitation and Western blot analysis. In this study we have analyzed the mutation and expression data of The Cancer Genome Atlas (TCGA) database and found that CDK12 is highly expressed in lung cancer tissues. Clinical correlation analysis showed that high expression of CDK12 in NSCLC reduces patient survival, but its high expression is only related to early tumor progression and has no significant correlation with late tumor progression and metastasis. Furthermore, we present evidence that CDK12 depletion in lung cancer cell lines not only leads to the inhibition of cell growth and induces apoptosis but also inhibits tumor growth of NSCLC cells in vivo. CDK12 positively regulates the expression of the oncogene TBK1 in lung cancer cells. These results revealed that CDK12 affects the progression of non-small cell lung cancer through positive regulation of TBK1 expression, suggesting that CDK12 might be a potential molecular target for the treatment of non-small cell lung cancer.

Keywords:  Cyclin dependent kinases (CDK12); Non-small cell lung cancer; TANK-Binding kinase 1 (TBK1)

DOI:  https://doi.org/10.1016/j.mcp.2023.101923
Cytokine Growth Factor Rev. 2023 Jul 29. pii: S1359-6101(23)00035-7. [Epub ahead of print]

Role of exosomes in transferring chemoresistance through modulation of cancer glycolytic cell metabolism.

Mahrou Vahabi, Annalisa Comandatore, Marika A Franczak, Ryszard T Smolenski, Godefridus J Peters, Luca Morelli, Elisa Giovannetti.

  Chemoresistance constitute a major obstacle in cancer treatment, leading to limited options and decreased patient survival. Recent studies have revealed a novel mechanism of chemoresistance acquisition: the transfer of information via exosomes, small vesicles secreted by various cells. Exosomes play a crucial role in intercellular communication by carrying proteins, nucleic acids, and metabolites, influencing cancer cell behavior and response to treatment. One crucial mechanism of resistance is cancer metabolic reprogramming, which involves alterations in the cellular metabolic pathways to support the survival and proliferation of drug-resistant cancer cells. This metabolic reprogramming often includes increased glycolysis, providing cancer cells with the necessary energy and building blocks to evade the effects of chemotherapy. Notably, exosomes have been found to transport glycolytic enzymes, as identified in proteomic profiling, leading to the reprogramming of metabolic pathways, facilitating altered glucose metabolism and increased lactate production. As a result, they profoundly impact the tumor microenvironment, promoting tumor progression, survival, immune evasion, and drug resistance.Understanding the complexities of such exosome-mediated cell-to-cell communication might open new therapeutic avenues and facilitate biomarker development in managing cancers characterized by aggressive glycolytic features. Moreover, given the intricate nature of metabolic abnormalities combining future exosome-based-targeted therapies with existing treatments like chemotherapy, immunotherapy, and targeted therapies holds promise for achieving synergistic effects to overcome resistance and improve cancer treatment outcomes.

Keywords:  Cancer metabolism; Cell-to-cell communication; Chemoresistance; Exosomes; Glycolysis

DOI:  https://doi.org/10.1016/j.cytogfr.2023.07.004
Heliyon. 2023 Aug;9(8): e18503

Prediction of prognosis and immunotherapy response in lung adenocarcinoma based on CD79A, DKK1 and VEGFC.

Qilong Zhang, Mingyuan Zhao, Shuangyan Lin, Qi Han, He Ye, Fang Peng, Li Li.

   Background: Tumor immune microenvironment (TIME) is crucial for tumor initiation, progression, and metastasis; however, its relationship with lung adenocarcinoma (LUAD) is unknown. Traditional predictive models screen for biomarkers that are too general and infrequently associated with immune genes.
Methods: RNA sequencing data of LUAD patients and immune-related gene sets were retrieved from public databases. Using the common genes shared by The Cancer Genome Atlas (TCGA) and Immunology Database and Analysis Portal (ImmPort), differential gene expression analysis, survival analysis, Lasso regression analysis, and univariate and multivariate Cox regression analyses were performed to generate a novel risk score model. LUAD cohort in International Cancer Genome Consortium (ICGC), GSE68465 cohort in Gene Expression Omnibus (GEO) and an immunohistochemical assay were used to validate the key genes constructed risk score. The LUAD-related prognosis, clinical indicators, immune infiltrate characteristics, response to immunotherapy, and response to chemotherapeutic agents in different risk groups were evaluated by CIBERSORT, ImmuCellAI, pRRophetic and other tools.
Results: The risk score model was constructed using CD79a molecule (CD79A), Dickkopf WNT signaling pathway inhibitor 1 (DKK1), and vascular endothelial growth factor C (VEGFC). High risk score was identified as a negative predictor for overall survival (OS) in subgroup analyses with tumor stage, TNM classification, therapy outcome, and ESTIMATE scores (P < 0.05). Low risk score was positively associated with plasma cells, memory B cells, CD8 T cells, regulatory T cells and γδT cells (P < 0.05). In low-risk group, programmed cell death 1 receptor (PD1), cytotoxic T-lymphocyte associated protein 4 (CTLA4), and lymphocyte activating 3 (LAG3) and indoleamine 2,3-dioxygenase (IDO) were more robustly expressed (P < 0.05). The treatment responses of immune checkpoint blockade (ICB) therapy and chemotherapy were likewise superior in low-risk group (P < 0.05). In immunohistochemical analysis, the tumor group had significantly higher levels of CD79A, DKK1, and VEGFC than the adjacent normal group (P < 0.01).
Conclusions: CD79A, DKK1 and VEGFC are important differential genes related to LUAD, risk score could reliably predict prognosis, composition of TIME and immunotherapy responses in LUAD patients. The excellent performance of the risk model shows its strong and broad application potential.

Keywords:  CD79A; DKK1; Lung adenocarcinoma; Prognosis; Tumor immune microenvironment; VEGFC

DOI:  https://doi.org/10.1016/j.heliyon.2023.e18503
Cell Rep. 2023 Aug 01. pii: S2211-1247(23)00910-5. [Epub ahead of print]42(8): 112899

Modulation of host glutamine anabolism enhances the sensitivity of small cell lung cancer to chemotherapy.

Manabu Kodama, Gouji Toyokawa, Osamu Sugahara, Shigeaki Sugiyama, Naoki Haratake, Yuichi Yamada, Reona Wada, Shinkichi Takamori, Mototsugu Shimokawa, Tomoyoshi Takenaka, Tetsuzo Tagawa, Hiroki Kittaka, Takeshi Tsuruda, Kentaro Tanaka, Yushiro Komatsu, Keisuke Nakata, Yuri Imado, Koji Yamazaki, Isamu Okamoto, Yoshinao Oda, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Hideyuki Shimizu, Tomoharu Yoshizumi, Keiichi I Nakayama.

  Small cell lung cancer (SCLC) is one of the deadliest human cancers, with a 5-year survival rate of ∼7%. Here, we performed a targeted proteomics analysis of human SCLC samples and thereby identified hypoxanthine phosphoribosyltransferase 1 (HPRT1) in the salvage purine synthesis pathway as a factor that contributes to SCLC malignancy by promoting cell survival in a glutamine-starved environment. Inhibition of HPRT1 by 6-mercaptopurine (6-MP) in combination with methotrexate (MTX), which blocks the de novo purine synthesis pathway, attenuated the growth of SCLC in mouse xenograft models. Moreover, modulation of host glutamine anabolism with the glutamine synthetase inhibitor methionine sulfoximine (MSO) in combination with 6-MP and MTX treatment resulted in marked tumor suppression and prolongation of host survival. Our results thus suggest that modulation of host glutamine anabolism combined with simultaneous inhibition of the de novo and salvage purine synthesis pathways may be of therapeutic benefit for SCLC.

Keywords:  CP: Cancer; HPRT1; host glutamine metabolism; nucleotide biosynthesis; salvage pathway; small cell lung cancer

DOI:  https://doi.org/10.1016/j.celrep.2023.112899
Heliyon. 2023 Aug;9(8): e17400

Predictive value of the prognostic nutritional index in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

Handai Xia, Wengang Zhang, Qi Zheng, Yuqing Zhang, Xin Mu, Chenxi Wei, Xiuwen Wang, Yanguo Liu.

   Purpose: The prognostic nutritional index (PNI), which is derived from the albumin concentration and absolute lymphocyte number, is an effective indicator of cancer patients' nutritional and immunological status. According to multiple studies, PNI was strongly linked to the prognosis of patients with non-small cell lung cancer (NSCLC). The predictive value of PNI for survival outcomes in NSCLC patients receiving immune checkpoint inhibitors (ICIs) is still in dispute at present. This meta-analysis is devoted to fill this information gap and investigate the predictive ability of PNI in NSCLC patients treated with ICIs.
Methods: The PubMed, Embase, Cochrane Library databases, and conference proceedings were searched for eligible studies without language restriction. Overall survival (OS) and progression-free survival (PFS) were included. The predictive value of PNI was estimated using hazard ratios and their 95% confidence intervals.
Results: Thirteen relevant retrospective cohort studies were included and these studies included 1119 patients with stage III-IV NSCLC. Lower PNI status was found to be an independent risk factor for worse survival outcomes in patients with NSCLC (OS HR = 2.68; 95%CI: 1.76-4.06; P < 0.0001; PFS HR = 1.84; 95%CI: 1.39-2.42; P < 0.0001). According to the subgroup analysis, PNI was similarly connected to OS in most subgroups of NSCLC patients receiving ICIs, except for those receiving chemoimmunotherapy or first-line treatment, and those with a cut-off value < 45.
Conclusion: Our findings indicated that lower PNI was associated with poorer prognosis in NSCLC patients undergoing ICI therapy. Further prospective research with bigger patient groups is required.
Systematic Review Registration: International Prospective Register of Systematic Reviews (PROSPERO), identifier CRD42022327528.

Keywords:  Meta-analysis; Non-small cell lung cancer; Prognostic nutritional index

DOI:  https://doi.org/10.1016/j.heliyon.2023.e17400
Oncology. 2023 Aug 01.

Lipid metabolism pathway genes and lung cancer: ACADSB rs12220683G>C is associated with better survival outcome in patients with non-small cell lung cancer.

Seung Soo Yoo, Sook Kyung Do, Jin Eun Choi, Hyo-Gyoung Kang, Mi Jeong Hong, Jang Hyuck Lee, Won Kee Lee, Young Woo Do, Eung Bae Lee, Ji Eun Park, Sun Ha Choi, Hyewon Seo, Yong Hoon Lee, Jaehee Lee, Shin Yup Lee, Seung Ick Cha, Chang Ho Kim, Jae Yong Park.

Altered lipid metabolism has been reported to be associated with prognosis in multiple cancers. This study aimed to investigate the association of polymorphisms in lipid metabolism pathway genes with survival outcomes in patients with surgically resected non-small cell lung cancer (NSCLC). In total, 744 patients with surgically resected NSCLC (380 in the discovery cohort and 364 in the validation cohort) were included in this study. Among the 176 investigated polymorphisms, ACADSB rs10902859G>A was associated with significantly better overall survival (OS) in the discovery, validation, and combined cohorts. ACADSB rs10902859G>A was located in the repressed region and had strong linkage disequilibrium (D' = 1.00 and r2 = 0.94), with rs12220683G>C located in the H3K4me3 peak region, which indicates the presence of active promoters. ACADSB rs12220683G>C was also associated with better OS in the discovery, validation, and combined cohorts (in a dominant model; adjusted hazard ratio [aHR] = 0.53, 95% confidence interval [CI] = 0.30-0.94, P = 0.03; aHR = 0.37, 95% CI = 0.15-0.89, P = 0.03; and aHR = 0.47, 95% CI = 0.29-0.75, P = 0.002, respectively). In vitro luciferase assay demonstrated that the promoter activity of ACADSB was significantly increased in the rs12220683 variant C allele compared with that in the wild G allele (P = 3 × 10-5). These results suggest that ACADSB rs12220683G>C increases promoter activity and that increased ACADSB expression may result in better OS in patients with surgically resected NSCLC.

DOI: https://doi.org/10.1159/000533156