bims-meluca 2022-03-27 papers

Pharmaceuticals (Basel). 2022 Mar 21. pii: 381. [Epub ahead of print]15(3):

Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial-Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells.

Pedro Barrios-Bernal, Norma Hernandez-Pedro, Mario Orozco-Morales, Rubí Viedma-Rodríguez, José Lucio-Lozada, Federico Avila-Moreno, Andrés F Cardona, Rafael Rosell, Oscar Arrieta.

The combination of metformin and TKIs for non-small cell lung cancer has been proposed as a strategy to overcome resistance of neoplastic cells induced by several molecular mechanisms. This study sought to investigate the effects of a second generation TKI afatinib, metformin, or their combination on three adenocarcinoma lung cancer cell lines with different EGFRmutation status. A549, H1975, and HCC827 cell lines were treated with afatinib, metformin, and their combination for 72 h. Afterwards, several parameters were assessed including cytotoxicity, interactions, apoptosis, and EGFR protein levels at the cell membrane and several glycolytic, oxidative phosphorylation (OXPHOS), and EMT expression markers. All cell lines showed additive to synergic interactions for the induction of cytotoxicity caused by the tested combination, as well as an improved pro-apoptotic effect. This effect was accompanied by downregulation of glycolytic, EMT markers, a significant decrease in glucose uptake, extracellular lactate, and a tendency towards increased OXPHOS subunits expression. Interestingly, we observed a better response to the combined therapy in lung cancer cell lines A549 and H1975, which normally have low affinity for TKI treatment. Findings from this study suggest a sensitization to afatinib therapy by metformin in TKI-resistant lung cancer cells, as well as a reduction in cellular glycolytic phenotype.

Keywords: EGFR; afatinib–metformin; epithelial–mesenchymal transition; glycolysis; lung cancer; oxidative phosphorylation

DOI: https://doi.org/10.3390/ph15030381

Cancers (Basel). 2022 Mar 11. pii: 1440. [Epub ahead of print]14(6):

Exploring the Impact of the Obesity Paradox on Lung Cancer and Other Malignancies.

Lindsay Joyce Nitsche, Sarbajit Mukherjee, Kareena Cheruvu, Cathleen Krabak, Rohit Rachala, Kalyan Ratnakaram, Priyanka Sharma, Maddy Singh, Sai Yendamuri.

There is a paradoxical relationship between obesity, as measured by BMI, and many types of cancer, including non-small-cell lung cancer. Obese non-small-cell lung cancer patients have been shown to fare better than their non-obese counterparts. To analyze the multifaceted effects of obesity on oncologic outcomes, we reviewed the literature on the obesity paradox, methods to measure adiposity, the obesity-related derangements in immunology and metabolism, and the oncologic impact of confounding variables such as gender, smoking, and concomitant medications such as statins and metformin. We analyzed how these aspects may contribute to the obesity paradox and cancer outcomes with a focus on lung cancer. We concluded that the use of BMI to measure adiposity is limited and should be replaced by a method that can differentiate abdominal obesity. We also concluded that the concomitant metabolic and immunologic derangements caused by obesity contribute to the obesity paradox. Medications, gender, and smoking are additional variables that impact oncologic outcomes, and further research needs to be performed to solidify the mechanisms.

Keywords: BMI; lung cancer; obesity; obesity paradox

DOI: https://doi.org/10.3390/cancers14061440

PLoS One. 2022 ;17(3): e0266070

Autophagy characteristics and establishment of autophagy prognostic models in lung adenocarcinoma and lung squamous cell carcinoma.

Zhubei Chen, Hui Xiong, Hao Shen, Qingsheng You.

BACKGROUND: Non-small cell lung cancer (NSCLC), which makes up the majority of lung cancers, remains one of the deadliest malignancies in the world. It has a poor prognosis due to its late detection and lack of response to chemoradiaiton. Therefore, it is urgent to find a new prognostic marker.METHODS: We evaluated biological function and immune cell infiltration in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients from TCGA and GEO databases between different clusters based on autophagy related hub genes. Autophagy scores were used to assess the degree of autophagy in each individual by using component analysis.
RESULTS: Three different clusters were obtained. Gene set variation analysis, single-sample gene set enrichment analysis and survive analysis showed differences among these three clusters. We demonstrated that the autophagy score of each patient could predict tumor stage and prognosis. Patients with a high autophagy score had a better prognosis, higher immune infiltration, and were more sensitive to immunotherapy and conventional chemotherapy.
CONCLUSION: It was uncovered that autophagy played an irreplaceable role in NSCLC. Quantified autophagy scores for each NSCLC patient would help guide effective treatment strategies.

DOI: https://doi.org/10.1371/journal.pone.0266070

Am J Physiol Cell Physiol. 2022 Mar 23.

IL-17A contributes skeletal muscle atrophy in lung cancer-induced cachexia via JAK2/STAT3 pathway.

Lin Ying, Yinan Yao, Handi Lv, Guohua Lu, Qin Zhang, Yunmei Yang, Jianying Zhou.

Cachexia is a complex metabolic syndrome that occurs in approximately 50% of patients with cancer. Skeletal muscle atrophy is the primary clinical feature. Interleukin (IL)-17A, a pro-inflammatory factor, plays an important role in many chronic inflammatory diseases. Here, we describe a novel signaling pathway through which IL-17A induced muscle atrophy.We conducted a retrospective clinical study to investigate the relationship between IL-17A and the skeletal muscle index in patients with lung adenocarcinoma. We also investigated the involvement of JAK2/STAT3 signaling pathway regarding the main features of cachexia by injecting Lewis lung carcinoma (LLC) cells into C57BL/6 mice as a model to replicate cancer-induced cachexia. In vitro, C2C12 myotubes were treated with recombinant IL-17A, anti-IL-17A monoclonal antibody, STAT3 inhibitor AG490, and LLC-conditioned medium. Cell viability and aging was also evaluated. We found in cancer conditions, increased serum levels of IL-17A were related to muscle wasting. JAK2/STAT3 phosphorylation was observed in the muscle of LLC tumor-bearing mice, accompanied by decreased MHC/Myog levels and increased MuRF1/Atrogin-1 levels. Administration of anti-IL-17A monoclonal antibody and AG490 slowed muscle atrophy development. Consistent with the in vivo findings, C2C12 myotubes treated with IL-17A and LLC-conditioned medium demonstrated phosphorylated JAK2/STAT3 signaling, resulting in MHC loss and myotube atrophy. IL-17A also inhibited C2C12 cell proliferation, cell cycle breaking, and cellular senescence. Our results identify phosphorylation of IL-17A/JAK2/STAT3 signaling pathway appears to be an important component in the pathogenesis of LLC tumor-induced cachexia. Targeted therapy of IL-17A may be a promising approach to reduce skeletal muscle loss of patients with cancer.

Keywords: Cancer cachexia; IL-17A; Inflammation; Muscle atrophy; STAT3

DOI: https://doi.org/10.1152/ajpcell.00463.2021

Front Nutr. 2022 ;9 792577

Effects of Diabetes on Inflammatory Status and Prognosis in Cancer Patients.

Xiangliang Liu, Kaiwen Zheng, Wei Ji, Wenxin Zhang, Yuguang Li, Mingyang Liu, Jiuwei Cui, Wei Li.

Background: Cancer and diabetes mellitus (DM) are prevalent, but there still a lack of convinced evidence clearly explaining the extent of the effect of diabetes in cancer.Data and Methods: Clinical data of 2,929 cancer patients were collected. Diabetes were diagnosed according to the Diabetes Diagnosis and Treatment Criteria. BMI was classified by the BMI standards for Chinese adults published by the Working Group on Obesity. All involved patients were classified into the non-DM group and DM group. The Kaplan-Meier curve, log-rank test and Cox regression analyses were used to perform survival analysis.
Results: Compared with non-DM patients, OS in DM patients was significant shorter in lung cancer (HR = 2.076, P = 0.001 in early stage; HR = 2.118, P < 0.001 in advanced stage), digestive tract cancer (HR = 1.768, P = 0.020 in early stage; HR = 2.454, P = 0.005 in advanced stage), leukemia (HR = 2.636, P < 0.001), breast cancer (HR = 2.495, P = 0.047 in early stage; HR = 2.929, P = 0.019 in advanced stage) and liver cancer (HR = 3.086, P < 0.001 in early stage; HR = 2.219, P = 0.049 in advanced stage). DM negatively influenced OS when the BMI was within the normal range in overall cancer (HR = 2.468, P < 0.001), lung cancer (HR = 2.297, P < 0.001), digestive tract cancer (HR = 2.354, P < 0.001), liver cancer (HR = 2.406, P = 0.001), leukemia (HR = 4.039, P < 0.001) and breast cancer (HR = 4.222, P = 0.008). Among those with BMI ≥ 24 kg/m2, DM played a role only in lung cancer (HR = 1.597, P = 0.037).
Conclusions: Patients with diabetes tend to combine worse body composition and inflammation status, and that glycemic control can ameliorate the impairment of diabetes to some extent.

Keywords: BMI; cancer; diabetes; inflammation; prognosis

DOI: https://doi.org/10.3389/fnut.2022.792577