bims-almceb 2021-09-26 papers

Cancer Control. 2021 Jan-Dec;28:28 10732748211041243

Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy.

Karolina Kozal, Paweł Jóźwiak, Anna Krześlak.

In the 1920s, Otto Warburg observed the phenomenon of altered glucose metabolism in cancer cells. Although the initial hypothesis suggested that the alteration resulted from mitochondrial damage, multiple studies of the subject revealed a precise, multistage process rather than a random pattern. The phenomenon of aerobic glycolysis emerges not only from mitochondrial abnormalities common in cancer cells, but also results from metabolic reprogramming beneficial for their sustenance. The Warburg effect enables metabolic adaptation of cancer cells to grow and proliferate, simultaneously enabling their survival in hypoxic conditions. Altered glucose metabolism of cancer cells includes, inter alia, qualitative and quantitative changes within glucose transporters, enzymes of the glycolytic pathway, such as hexokinases and pyruvate kinase, hypoxia-inducible factor, monocarboxylate transporters, and lactate dehydrogenase. This review summarizes the current state of knowledge regarding inhibitors of cancer glucose metabolism with a focus on their clinical potential. The altered metabolic phenotype of cancer cells allows for targeting of specific mechanisms, which might improve conventional methods in anti-cancer therapy. However, several problems such as drug bioavailability, specificity, toxicity, the plasticity of cancer cells, and heterogeneity of cells in tumors have to be overcome when designing therapies based on compounds targeted in cancer cell energy metabolism.

Keywords: aerobic glycolysis; anti-cancer therapy; glucose transporters; hypoxia-inducible factor; inhibitors; lactate dehydrogenase; monocarboxylate transporters; pyruvate kinase

DOI: https://doi.org/10.1177/10732748211041243

Leukemia. 2021 Sep 24.

Mitochondrial metabolism as a potential therapeutic target in myeloid leukaemia.

Lucie de Beauchamp, Ekaterini Himonas, G Vignir Helgason.

While the understanding of the genomic aberrations that underpin chronic and acute myeloid leukaemia (CML and AML) has allowed the development of therapies for these diseases, limitations remain. These become apparent when looking at the frequency of treatment resistance leading to disease relapse in leukaemia patients. Key questions regarding the fundamental biology of the leukaemic cells, such as their metabolic dependencies, are still unresolved. Even though a majority of leukaemic cells are killed during initial treatment, persistent leukaemic stem cells (LSCs) and therapy-resistant cells are still not eradicated with current treatments, due to various mechanisms that may contribute to therapy resistance, including cellular metabolic adaptations. In fact, recent studies have shown that LSCs and treatment-resistant cells are dependent on mitochondrial metabolism, hence rendering them sensitive to inhibition of mitochondrial oxidative phosphorylation (OXPHOS). As a result, rewired energy metabolism in leukaemic cells is now considered an attractive therapeutic target and the significance of this process is increasingly being recognised in various haematological malignancies. Therefore, identifying and targeting aberrant metabolism in drug-resistant leukaemic cells is an imperative and a relevant strategy for the development of new therapeutic options in leukaemia. In this review, we present a detailed overview of the most recent studies that present experimental evidence on how leukaemic cells can metabolically rewire, more specifically the importance of OXPHOS in LSCs and treatment-resistant cells, and the current drugs available to target this process. We highlight that uncovering specific energy metabolism dependencies will guide the identification of new and more targeted therapeutic strategies for myeloid leukaemia.

DOI: https://doi.org/10.1038/s41375-021-01416-w

Front Oncol. 2021 ;11 698023

The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer.

Chang Liu, Ying Jin, Zhimin Fan.

Although chemotherapy can improve the overall survival and prognosis of cancer patients, chemoresistance remains an obstacle due to the diversity, heterogeneity, and adaptability to environmental alters in clinic. To determine more possibilities for cancer therapy, recent studies have begun to explore changes in the metabolism, especially glycolysis. The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically, even under normoxia, which contributes to chemoresistance. However, the association between glycolysis and chemoresistance and molecular mechanisms of glycolysis-induced chemoresistance remains unclear. This review describes the mechanism of glycolysis-induced chemoresistance from the aspects of glycolysis process, signaling pathways, tumor microenvironment, and their interactions. The understanding of how glycolysis induces chemoresistance may provide new molecular targets and concepts for cancer therapy.

Keywords: Warburg effect; chemoresistance; signaling pathway; transporters and key enzymes of glycolysis; tumor microenvironment

DOI: https://doi.org/10.3389/fonc.2021.698023

Anticancer Drugs. 2021 Sep 17.

Warburg and pasteur phenotypes modulate cancer behavior and therapy.

Caner Karaca, Atilla Tokatli, Anja Tokatli, Aslihan Karadag, Gizem Calibasi-Kocal.

Energetic pathways combine in the heart of metabolism. These essential routes supply energy for biochemical processes through glycolysis and oxidative phosphorylation. Moreover, they support the synthesis of various biomolecules employed in growth and survival over branching pathways. Yet, cellular energetics are often misguided in cancers as a result of the mutations and altered signaling. As nontransformed and Pasteur-like cells metabolize glucose through oxidative respiration when only oxygen is sufficient, some cancer cells bypass this metabolic switch and run glycolysis at higher rates even in the presence of oxygen. The phenomenon is called aerobic glycolysis or the Warburg effect. An increasing number of studies indicate that both Warburg and Pasteur phenotypes are recognized in the cancer microenvironment and take vital roles in the regulation of drug resistance mechanisms such as redox homeostasis, apoptosis and autophagy. Therefore, the different phenotypes call for different therapeutic approaches. Combined therapies targeting energy metabolism grant new opportunities to overcome the challenges. Nevertheless, new biomarkers emerge to classify the energetic subtypes, thereby the cancer therapy, as our knowledge in coupling energy metabolism with cancer behavior grows.

DOI: https://doi.org/10.1097/CAD.0000000000001236

Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00688-2. [Epub ahead of print]81(18): 3786-3802.e13

Mitochondrial-derived compartments facilitate cellular adaptation to amino acid stress.

Max-Hinderk Schuler, Alyssa M English, Tianyao Xiao, Thane J Campbell, Janet M Shaw, Adam L Hughes.

Amino acids are essential building blocks of life. However, increasing evidence suggests that elevated amino acids cause cellular toxicity associated with numerous metabolic disorders. How cells cope with elevated amino acids remains poorly understood. Here, we show that a previously identified cellular structure, the mitochondrial-derived compartment (MDC), functions to protect cells from amino acid stress. In response to amino acid elevation, MDCs are generated from mitochondria, where they selectively sequester and deplete SLC25A nutrient carriers and their associated import receptor Tom70 from the organelle. Generation of MDCs promotes amino acid catabolism, and their formation occurs simultaneously with transporter removal at the plasma membrane via the multivesicular body (MVB) pathway. The combined loss of vacuolar amino acid storage, MVBs, and MDCs renders cells sensitive to high amino acid stress. Thus, we propose that MDCs operate as part of a coordinated cell network that facilitates amino acid homeostasis through post-translational nutrient transporter remodeling.

Keywords: MDC; Tom70; amino acid; lysosome; mitochondria; nutrient carrier; vacuole

DOI: https://doi.org/10.1016/j.molcel.2021.08.021

Mitochondrion. 2021 Sep 15. pii: S1567-7249(21)00121-5. [Epub ahead of print]

Mitofusin 2: A Link Between Mitochondrial Function and Substrate Metabolism?

Janna M Emery, Rudy M Ortiz.

Mitochondria are dynamic, interactive organelles that connect cellular signaling and whole-cell homeostasis. This "mitochatting" allows the cell to receive information about the mitochondria's condition before accommodating energy demands. Mitofusin 2 (Mfn2), an outer mitochondrial membrane fusion protein specializes in mediating mitochondrial homeostasis. Early studies defined the biological significance of Mfn2, latter studies highlighted its role in substrate metabolism. However, determining Mfn2 potential to contribute to energy homeostasis needs study. This review summarizes current literature on mitochondrial metabolic processes, dynamics, and evidence of interactions among Mfn2 and regulatory processes that may link Mfn2's role in maintaining mitochondrial function and substrate metabolism.

Keywords: fatty acid oxidation; fission; fusion; glycolysis; mitochondrial dynamics; mitophagy

DOI: https://doi.org/10.1016/j.mito.2021.09.003

Biochim Biophys Acta Mol Basis Dis. 2021 Sep 15. pii: S0925-4439(21)00201-5. [Epub ahead of print] 166268

GPX1-associated prognostic signature predicts poor survival in patients with acute myeloid leukemia and involves in immunosuppression.

Jian Zhang, YuHui Peng, Yan He, Yan Xiao, Qinrong Wang, Yan Zhao, Tin Zhang, Changxue Wu, Yuan Xie, Jianjiang Zhou, Wenfeng Yu, Deqin Lu, Hua Bai, Tenxiang Chen, Penxiang Guo, Qifang Zhang.

OBJECTIVE: Treatment of acute myeloid leukemia (AML) remains a challenge. It is urgent to understand the microenvironment to improve therapy and prognosis.
METHODS: Bioinformatics methods were used to analyze transcription expression profile of AML patient samples with complete clinical information from UCSC Xena TCGA-AML datasets and validate with GEO datasets. Western blot, qPCR, RNAi and CCK8 assay were used to assay the effect of GPX1 expression on AML cell viability and the expression of genes of interest.
RESULTS: Our analyses revealed that highly expressed GPX1 in AML patients links to unfavorable prognosis. GPX1 expression was positively associated with not only fraction levels of myeloid-derived suppressor cells (MDSCs), monocytes and T cell exhaustion, the expression levels of MDSC markers, MDSC-promoting CCR2 and immune inhibitory checkpoints (TIM3/Gal-9, SIRPα and VISTA), but also negatively with low fraction levels of CD4+ and CD8+ T cells. Silencing GPX1 expression reduced AML cell viability and CCR2 expression. Moreover, GPX1-targetd kinases were PKC family, SRC family, SYK and PAK1, which promote AML progression and the resistance to therapy. Furthermore, Additionally, GPX1-associated prognostic signature (GPS) is an independent risk factor with high area under curve (AUC) values of receiver operating characteristic (ROC) curves. High risk group based on GPS enriched not only with endocytosis which transfers mitochondria to favor AML cell survival in response to chemotherapy, but also NOTCH，WNT and TLR signaling which promote therapy resistance.
CONCLUSION: Our results revealed the significant involvement of GPX1 in AML immunosuppression via and provided a prognostic signature for AML patients.

Keywords: CCR2; GPX1; SIRPα/CD47; TIM3/Gal-9; VISTA; acute myeloid leukemia; immunosuppresion; myeloid derived suppressor cells; prognosis

DOI: https://doi.org/10.1016/j.bbadis.2021.166268

Cancer Drug Resist. 2020 ;3 959-979

Genomic stability at the coding regions of the multidrug transporter gene ABCB1: insights into the development of alternative drug resistance mechanisms in human leukemia cells.

Kevin G Chen, George E Duran, Mark J Mogul, Yan C Wang, Kevin L Ross, Jean-Pierre Jaffrézou, Lyn M Huff, Kory R Johnson, Tito Fojo, Norman J Lacayo, Branimir I Sikic.

Aim: Despite considerable efforts to reverse clinical multidrug resistance (MDR), targeting the predominant multidrug transporter ABCB1/P-glycoprotein (P-gp) using small molecule inhibitors has been unsuccessful, possibly due to the emergence of alternative drug resistance mechanisms. However, the non-specific P-gp inhibitor cyclosporine (CsA) showed significant clinical benefits in patients with acute myeloid leukemia (AML), which likely represents the only proof-of-principle clinical trial using several generations of MDR inhibitors. Nevertheless, the mutational mechanisms that may underlie unsuccessful MDR modulation by CsA are not elucidated because of the absence of CsA-relevant cellular models. In this study, our aims were to establish CsA-resistant leukemia models and to examine the presence or absence of ABCB1 exonic mutations in these models as well as in diverse types of human cancer samples including AMLs.
Methods: Drug-resistant lines were established by stepwise drug co-selection and characterized by drug sensitivity assay, rhodamine-123 accumulation, [3H]-labeled drug export, ABCB1 cDNA sequencing, and RNase protection assay. The genomic stability of the ABCB1 coding regions was evaluated by exome sequencing analysis of variant allele frequencies in human populations. Moreover, the mutational spectrum of ABCB1 was further assessed in diverse types of cancer samples including AMLs in the Cancer Genome Atlas (TCGA) at the National Cancer Institute.
Results: We report the development of two erythroleukemia variants, RVC and RDC, which were derived by stepwise co-selection of K562/R7 drug-resistant leukemia cells with the etoposide-CsA and doxorubicin-CsA drug combinations, respectively. Interestingly, both RVC and RDC cell lines, which retained P-gp expression, showed altered multidrug-resistant phenotypes that were resistant to CsA modulation. Strikingly, no mutations were found in the ABCB1 coding regions in these variant cells even under long-term stringent drug selection. Genomically, ABCB1 displayed relatively low variant allele frequencies in human populations when compared with several ABC superfamily members. Moreover, ABCB1 also exhibited a very low mutational frequency in AMLs compared with all types of human cancer. In addition, we found that CsA played a role in undermining the selection of highly drug-resistant cells via induction of low-level and unstable drug resistance.
Conclusion: Our data indicate that ABCB1 coding regions are genomically stable and relatively resistant to drug-induced mutations. Non-ABCB1 mutational mechanisms are responsible for the drug-resistant phenotypes in both RVC and RDC cell lines, which are also prevalent in clinical AML patients. Accordingly, we propose several relevant models that account for the development of alternative drug resistance mechanisms in the absence of ABCB1 mutations.

Keywords: ABCB1; Cancer; P-glycoprotein; cyclosporine; leukemia; multidrug resistance; mutation

DOI: https://doi.org/10.20517/cdr.2020.51