bims-almceb 2021-05-02 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021–05–02
thirteen papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

ARRB1 Regulates Metabolic Reprogramming to Promote Glycolysis in Stem Cell-Like Bladder Cancer Cells.
Glutamine deficiency promotes stemness and chemoresistance in tumor cells through DRP1-induced mitochondrial fragmentation.
Mitochondria Turnover and Lysosomal Function in Hematopoietic Stem Cell Metabolism.
Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine.
Precision medicine in myeloid malignancies.
Editorial: How Do Metabolism, Angiogenesis, and Hypoxia Modulate Resistance?
Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines.
Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling.
Oxidative Stress in Cancer Cell Metabolism.
Interplay between Metabolism Reprogramming and Epithelial-to-Mesenchymal Transition in Cancer Stem Cells.
Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade.
Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer.
Inflammatory Markers in Cancer Immunotherapy.

Cancers (Basel). 2021 Apr 10. pii: 1809. [Epub ahead of print]13(8):

ARRB1 Regulates Metabolic Reprogramming to Promote Glycolysis in Stem Cell-Like Bladder Cancer Cells.

Kenza Mamouni, Jeongheun Kim, Bal L Lokeshwar, Georgios Kallifatidis.

  β-arrestin 1 (ARRB1) is a scaffold protein that regulates signaling downstream of G protein-coupled receptors (GPCRs). In the current work, we investigated the role of ARRB1 in regulating the metabolic preference of cancer stem cell (CSC)-like cells in bladder cancer (BC). We show that ARRB1 is crucial for spheroid formation and tumorigenic potential. Furthermore, we measured mitochondrial respiration, glucose uptake, glycolytic rate, mitochondrial/glycolytic ATP production and fuel oxidation in previously established ARRB1 knock out (KO) cells and corresponding controls. Our results demonstrate that depletion of ARRB1 decreased glycolytic rate and induced metabolic reprogramming towards oxidative phosphorylation. Mechanistically, the depletion of ARRB1 dramatically increased the mitochondrial pyruvate carrier MPC1 protein levels and reduced the glucose transporter GLUT1 protein levels along with glucose uptake. Overexpression of ARRB1 in ARRB1 KO cells reversed the phenotype and resulted in the upregulation of glycolysis. In conclusion, we show that ARRB1 regulates the metabolic preference of BC CSC-like cells and functions as a molecular switch that promotes reprogramming towards glycolysis by negatively regulating MPC1 and positively regulating GLUT1/ glucose uptake. These observations open new therapeutic avenues for targeting the metabolic preferences of cancer stem cell (CSC)-like BC cells.

Keywords:  bladder cancer; cancer system cells; glucose transporter; metabolic reprograming; mitochondrial pyruvate carrier; β-arrestin 1

DOI:  https://doi.org/10.3390/cancers13081809
Cell Mol Life Sci. 2021 Apr 24.

Glutamine deficiency promotes stemness and chemoresistance in tumor cells through DRP1-induced mitochondrial fragmentation.

Parash Prasad, Sampurna Ghosh, Sib Sankar Roy.

  Glutamine is essential for maintaining the TCA cycle in cancer cells yet they undergo glutamine starvation in the core of tumors. Cancer stem cells (CSCs), responsible for tumor recurrence are often found in the nutrient limiting cores. Our study uncovers the molecular basis and cellular links between glutamine deprivation and stemness in the cancer cells. We showed that glutamine is dispensable for the survival of ovarian and colon cancer cells while it is required for their proliferation. Glutamine starvation leads to the metabolic reprogramming in tumor cells with enhanced glycolysis and unaltered oxidative phosphorylation. Production of reactive oxygen species (ROS) in glutamine limiting condition induces MAPK-ERK1/2 signaling pathway to phosphorylate dynamin-related protein-1(DRP1) at Ser616. Moreover, p-DRP1 promotes mitochondrial fragmentation and enhances numbers of CD44 and CD117/CD45 positive CSCs. Besides the established features of cancer stem cells, glutamine deprivation induces perinuclear localization of fragmented mitochondria and reduction in proliferation rate which are usually observed in CSCs. Treatment with glutaminase inhibitor (L-DON) mimics the effects of glutamine starvation without altering cell survival in in vitro as well as in in vivo model. Interestingly, the combinatorial treatment of L-DON with DRP1 inhibitor (MDiVi-1) reduces the stem cell population in tumor tissue in mouse model. Collectively our data suggest that glutamine deficiency in the core of tumors can increase the cancer stem cell population and the combination therapy with MDiVi-1 and L-DON is a useful approach to reduce CSCs population in tumor.

Keywords:  Glutaminase; Glutamine metabolism; Mitochondrial fission; ROS; Tumor growth

DOI:  https://doi.org/10.1007/s00018-021-03818-6
Int J Mol Sci. 2021 Apr 28. pii: 4627. [Epub ahead of print]22(9):

Mitochondria Turnover and Lysosomal Function in Hematopoietic Stem Cell Metabolism.

Makiko Mochizuki-Kashio, Hiroko Shiozaki, Toshio Suda, Ayako Nakamura-Ishizu.

  Hematopoietic stem cells (HSCs) reside in a hypoxic microenvironment that enables glycolysis-fueled metabolism and reduces oxidative stress. Nonetheless, metabolic regulation in organelles such as the mitochondria and lysosomes as well as autophagic processes have been implicated as essential for the determination of HSC cell fate. This review encompasses the current understanding of anaerobic metabolism in HSCs as well as the emerging roles of mitochondrial metabolism and lysosomal regulation for hematopoietic homeostasis.

Keywords:  ROS; autophagy; folliculin; hematopoietic stem cells; lysosome; mitochondria

DOI:  https://doi.org/10.3390/ijms22094627
J Hematol Oncol. 2021 Apr 26. 14(1): 70

Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine.

Ralf Buettner, Le Xuan Truong Nguyen, Corey Morales, Min-Hsuan Chen, Xiwei Wu, Lisa S Chen, Dinh Hoa Hoang, Servando Hernandez Vargas, Vinod Pullarkat, Varsha Gandhi, Guido Marcucci, Steven T Rosen.

   BACKGROUND: BCL-2 inhibition through venetoclax (VEN) targets acute myeloid leukemia (AML) blast cells and leukemic stem cells (LSCs). Although VEN-containing regimens yield 60-70% clinical response rates, the vast majority of patients inevitably suffer disease relapse, likely because of the persistence of drug-resistant LSCs. We previously reported preclinical activity of the ribonucleoside analog 8-chloro-adenosine (8-Cl-Ado) against AML blast cells and LSCs. Moreover, our ongoing phase I clinical trial of 8-Cl-Ado in patients with refractory/relapsed AML demonstrates encouraging clinical benefit. Of note, LSCs uniquely depend on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. VEN inhibits OXPHOS in LSCs, which eventually may escape the antileukemic activity of this drug. FAO is activated in LSCs isolated from patients with relapsed AML.
METHODS: Using AML cell lines and LSC-enriched blast cells from pre-treatment AML patients, we evaluated the effects of 8-Cl-Ado, VEN and the 8-Cl-Ado/VEN combination on fatty acid metabolism, glycolysis and OXPHOS using liquid scintillation counting, a Seahorse XF Analyzer and gene set enrichment analysis (GSEA). Western blotting was used to validate results from GSEA. HPLC was used to measure intracellular accumulation of 8-Cl-ATP, the cytotoxic metabolite of 8-Cl-Ado. To quantify drug synergy, we created combination index plots using CompuSyn software. The log-rank Kaplan-Meier survival test was used to compare the survival distributions of the different treatment groups in a xenograft mouse model of AML.
RESULTS: We here report that VEN and 8-Cl-Ado synergistically inhibited in vitro growth of AML cells. Furthermore, immunodeficient mice engrafted with MV4-11-Luc AML cells and treated with the combination of VEN plus 8-Cl-Ado had a significantly longer survival than mice treated with either drugs alone (p ≤ 0.006). We show here that 8-Cl-Ado in the LSC-enriched population suppressed FAO by downregulating gene expression of proteins involved in this pathway and significantly inhibited the oxygen consumption rate (OCR), an indicator of OXPHOS. By combining 8-Cl-Ado with VEN, we observed complete inhibition of OCR, suggesting this drug combination cooperates in targeting OXPHOS and the metabolic homeostasis of AML cells.
CONCLUSION: Taken together, the results suggest that 8-Cl-Ado enhances the antileukemic activity of VEN and that this combination represents a promising therapeutic regimen for treatment of AML.

Keywords:  Acute myeloid leukemia; Fatty acid oxidation; Metabolism; Nucleoside analog; Oxidative phosphorylation

DOI:  https://doi.org/10.1186/s13045-021-01076-4
Semin Cancer Biol. 2021 Apr 22. pii: S1044-579X(21)00084-5. [Epub ahead of print]

Precision medicine in myeloid malignancies.

Jörg Westermann, Lars Bullinger.

  Myeloid malignancies have always been at the forefront of an improved understanding of the molecular pathogenesis of cancer. In accordance, over the last years, basic research focusing on the aberrations underlying malignant transformation of myeloid cells has provided the basis for precision medicine approaches and subsequently has led to the development of powerful therapeutic strategies. In this review article, we will recapitulate what has happened since in the 1980s the use of all-trans retinoic acid (ATRA), as a first targeted cancer therapy, has changed one of the deadliest leukemia subtypes, acute promyelocytic leukemia (APL), into one that can be cured without classical chemotherapy today. Similarly, imatinib, the first molecularly designed cancer therapy, has revolutionized the management of chronic myeloid leukemia (CML). Thus, targeted treatment approaches have become the paradigm for myeloid malignancy, but many questions still remain unanswered, especially how identical mutations can be associated with different phenotypes. This might be linked to the impact of the cell of origin, gene-gene interactions, or the tumor microenvironment including the immune system. Continuous research in the field of myeloid neoplasia has started to unravel the molecular pathways that are not only crucial for initial treatment response, but also resistance of leukemia cells under therapy. Ongoing studies focusing on leukemia cell vulnerabilities do already point to novel (targetable) "Achilles heels" that can further improve myeloid cancer therapy.

Keywords:  Acute Myeloid Leukemia (AML); Mastocytosis; Myelodysplastic Syndromes (MDS); Myeloid malignancy; Myeloproliferative Neoplasms (MPN); Precision medicine

DOI:  https://doi.org/10.1016/j.semcancer.2021.03.034
Front Oncol. 2021 ;11 671222

Editorial: How Do Metabolism, Angiogenesis, and Hypoxia Modulate Resistance?

Hiroshi Kondoh, Josep Castellvi, Matilde Esther LLeonart.



Keywords:  autophagy; cancer; cancer resistance; cancer stem cell; therapy

DOI:  https://doi.org/10.3389/fonc.2021.671222
BMC Cancer. 2021 Apr 30. 21(1): 481

Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines.

Jonas Parczyk, Jérôme Ruhnau, Carsten Pelz, Max Schilling, Hao Wu, Nicole Nadine Piaskowski, Britta Eickholt, Hartmut Kühn, Kerstin Danker, Andreas Klein.

   BACKGROUND: One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Furthermore, the likelihood of drug resistance is reduced. Distinct alterations in tumor metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy. Recently, we found evidence for synergism between dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, and the HIF-1α inhibitor PX-478. In this study, we aimed to analyse this synergism in cell lines of different cancer types and to identify the underlying biochemical mechanisms.
METHODS: The dose-dependent antiproliferative effects of the single drugs and their combination were assessed using SRB assays. FACS, Western blot and HPLC analyses were performed to investigate changes in reactive oxygen species levels, apoptosis and the cell cycle. Additionally, real-time metabolic analyses (Seahorse) were performed with DCA-treated MCF-7 cells.
RESULTS: The combination of DCA and PX-478 produced synergistic effects in all eight cancer cell lines tested, including colorectal, lung, breast, cervical, liver and brain cancer. Reactive oxygen species generation and apoptosis played important roles in this synergism. Furthermore, cell proliferation was inhibited by the combination treatment.
CONCLUSIONS: Here, we found that these tumor metabolism-targeting compounds exhibited a potent synergism across all tested cancer cell lines. Thus, we highly recommend the combination of these two compounds for progression to in vivo translational and clinical trials.

Keywords:  Cancer cell lines; Cancer therapy; Dichloroacetate; Drug combination; HIF-1α inhibition; Metabolism; PX-478; Synergism

DOI:  https://doi.org/10.1186/s12885-021-08186-9
Molecules. 2021 Apr 15. pii: 2303. [Epub ahead of print]26(8):

Pharmaceutical Drug Metformin and MCL1 Inhibitor S63845 Exhibit Anticancer Activity in Myeloid Leukemia Cells via Redox Remodeling.

Giedrė Valiulienė, Aida Vitkevičienė, Giedrė Skliutė, Veronika Borutinskaitė, Rūta Navakauskienė.

  Metabolic landscape and sensitivity to apoptosis induction play a crucial role in acute myeloid leukemia (AML) resistance. Therefore, we investigated the effect of metformin, a medication that also acts as an inhibitor of oxidative phosphorylation (OXPHOS), and MCL-1 inhibitor S63845 in AML cell lines NB4, KG1 and chemoresistant KG1A cells. The impact of compounds was evaluated using fluorescence-based metabolic flux analysis, assessment of mitochondrial Δψ and cellular ROS, trypan blue exclusion, Annexin V-PI and XTT tests for cell death and cytotoxicity estimations, also RT-qPCR and Western blot for gene and protein expression. Treatment with metformin resulted in significant downregulation of OXPHOS; however, increase in glycolysis was observed in NB4 and KG1A cells. In contrast, treatment with S63845 slightly increased the rate of OXPHOS in KG1 and KG1A cells, although it profoundly diminished the rate of glycolysis. Generally, combined treatment had stronger inhibitory effects on cellular metabolism and ATP levels. Furthermore, results revealed that treatment with metformin, S63845 and their combinations induced apoptosis in AML cells. In addition, level of apoptotic cell death correlated with cellular ROS induction, as well as with downregulation of tumor suppressor protein MYC. In summary, we show that modulation of redox-stress could have a potential anticancer activity in AML cells.

Keywords:  MCL-1 inhibitor S63845; acute myeloid leukemia (AML); metformin; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/molecules26082303
Antioxidants (Basel). 2021 Apr 22. pii: 642. [Epub ahead of print]10(5):

Oxidative Stress in Cancer Cell Metabolism.

Saniya Arfin, Niraj Kumar Jha, Saurabh Kumar Jha, Kavindra Kumar Kesari, Janne Ruokolainen, Shubhadeep Roychoudhury, Brijesh Rathi, Dhruv Kumar.

  Reactive oxygen species (ROS) are important in regulating normal cellular processes whereas deregulated ROS leads to the development of a diseased state in humans including cancers. Several studies have been found to be marked with increased ROS production which activates pro-tumorigenic signaling, enhances cell survival and proliferation and drives DNA damage and genetic instability. However, higher ROS levels have been found to promote anti-tumorigenic signaling by initiating oxidative stress-induced tumor cell death. Tumor cells develop a mechanism where they adjust to the high ROS by expressing elevated levels of antioxidant proteins to detoxify them while maintaining pro-tumorigenic signaling and resistance to apoptosis. Therefore, ROS manipulation can be a potential target for cancer therapies as cancer cells present an altered redox balance in comparison to their normal counterparts. In this review, we aim to provide an overview of the generation and sources of ROS within tumor cells, ROS-associated signaling pathways, their regulation by antioxidant defense systems, as well as the effect of elevated ROS production in tumor progression. It will provide an insight into how pro- and anti-tumorigenic ROS signaling pathways could be manipulated during the treatment of cancer.

Keywords:  NFκB pathway; angiogenesis; apoptosis; autophagy; cancer metabolism; drug resistance; metastasis; mitochondrial ROS; oxidative stress; tumor adaptation; tumor progression; tumor targeting; warburg effect

DOI:  https://doi.org/10.3390/antiox10050642
Cancers (Basel). 2021 Apr 20. pii: 1973. [Epub ahead of print]13(8):

Interplay between Metabolism Reprogramming and Epithelial-to-Mesenchymal Transition in Cancer Stem Cells.

Yoann Daniel, Elise Lelou, Caroline Aninat, Anne Corlu, Florian Cabillic.

  Tumor cells display important plasticity potential, which contributes to intratumoral heterogeneity. Notably, tumor cells have the ability to retrodifferentiate toward immature states under the influence of their microenvironment. Importantly, this phenotypical conversion is paralleled by a metabolic rewiring, and according to the metabostemness theory, metabolic reprogramming represents the first step of epithelial-to-mesenchymal transition (EMT) and acquisition of stemness features. Most cancer stem cells (CSC) adopt a glycolytic phenotype even though cells retain functional mitochondria. Such adaptation is suggested to reduce the production of reactive oxygen species (ROS), protecting CSC from detrimental effects of ROS. CSC may also rely on glutaminolysis or fatty acid metabolism to sustain their energy needs. Besides pro-inflammatory cytokines that are well-known to initiate the retrodifferentiation process, the release of catecholamines in the microenvironment of the tumor can modulate both EMT and metabolic changes in cancer cells through the activation of EMT transcription factors (ZEB1, Snail, or Slug (SNAI2)). Importantly, the acquisition of stem cell properties favors the resistance to standard care chemotherapies. Hence, a better understanding of this process could pave the way for the development of therapies targeting CSC metabolism, providing new strategies to eradicate the whole tumor mass in cancers with unmet needs.

Keywords:  cancer stem cell; catecholamines; cell plasticity; epithelial-to-mesenchymal transition; metabolism reprogramming

DOI:  https://doi.org/10.3390/cancers13081973
Mol Cell. 2021 Apr 21. pii: S1097-2765(21)00232-X. [Epub ahead of print]

Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade.

Xiaoming Dai, Xia Bu, Yang Gao, Jianping Guo, Jia Hu, Cong Jiang, Zhao Zhang, Kexin Xu, Jinzhi Duan, Shaohui He, Jinfang Zhang, Lixin Wan, Tianjie Liu, Xiaobo Zhou, Mien-Chie Hung, Gordon J Freeman, Wenyi Wei.

  Aberrant energy status contributes to multiple metabolic diseases, including obesity, diabetes, and cancer, but the underlying mechanism remains elusive. Here, we report that ketogenic-diet-induced changes in energy status enhance the efficacy of anti-CTLA-4 immunotherapy by decreasing PD-L1 protein levels and increasing expression of type-I interferon (IFN) and antigen presentation genes. Mechanistically, energy deprivation activates AMP-activated protein kinase (AMPK), which in turn, phosphorylates PD-L1 on Ser283, thereby disrupting its interaction with CMTM4 and subsequently triggering PD-L1 degradation. In addition, AMPK phosphorylates EZH2, which disrupts PRC2 function, leading to enhanced IFNs and antigen presentation gene expression. Through these mechanisms, AMPK agonists or ketogenic diets enhance the efficacy of anti-CTLA-4 immunotherapy and improve the overall survival rate in syngeneic mouse tumor models. Our findings reveal a pivotal role for AMPK in regulating the immune response to immune-checkpoint blockade and advocate for combining ketogenic diets or AMPK agonists with anti-CTLA4 immunotherapy to combat cancer.

Keywords:  AMPK; CMTM4; CTLA-4; EZH2; PD-L1; energy stress; glucose; immune checkpoint; ketogenic diet; phosphorylation

DOI:  https://doi.org/10.1016/j.molcel.2021.03.037
Metabolites. 2021 Apr 01. pii: 216. [Epub ahead of print]11(4):

Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer.

Mio Harachi, Kenta Masui, Webster K Cavenee, Paul S Mischel, Noriyuki Shibata.

  Metabolic reprogramming is an emerging hallmark of cancer and is driven by abnormalities of oncogenes and tumor suppressors. Accelerated metabolism causes cancer cell aggression through the dysregulation of rate-limiting metabolic enzymes as well as by facilitating the production of intermediary metabolites. However, the mechanisms by which a shift in the metabolic landscape reshapes the intracellular signaling to promote the survival of cancer cells remain to be clarified. Recent high-resolution mass spectrometry-based proteomic analyses have spotlighted that, unexpectedly, lysine residues of numerous cytosolic as well as nuclear proteins are acetylated and that this modification modulates protein activity, sublocalization and stability, with profound impact on cellular function. More importantly, cancer cells exploit acetylation as a post-translational protein for microenvironmental adaptation, nominating it as a means for dynamic modulation of the phenotypes of cancer cells at the interface between genetics and environments. The objectives of this review were to describe the functional implications of protein lysine acetylation in cancer biology by examining recent evidence that implicates oncogenic signaling as a strong driver of protein acetylation, which might be exploitable for novel therapeutic strategies against cancer.

Keywords:  epigenetics; mechanistic target of rapamycin (mTOR) complexes; metabolic reprogramming; microenvironment; protein acetylation

DOI:  https://doi.org/10.3390/metabo11040216
Biology (Basel). 2021 Apr 13. pii: 325. [Epub ahead of print]10(4):

Inflammatory Markers in Cancer Immunotherapy.

Deepak Ravindranathan, Viraj A Master, Mehmet Asim Bilen.

  Chronic inflammation is considered a major risk factor for cancer formation. Inflammation within the tumor environment plays a role in its response to therapy, growth, and prognosis. Cancer associated inflammation is known to occur in the tumor microenvironment and in the systemic circulation, and is correlated with disease progression and prognosis in many cancers. Blood cells such as neutrophils, lymphocytes, platelets, and circulating proteins such as C-reactive protein, and interleukins, such as IL-6, have been associated with inflammatory responses, which contribute to tumorigenesis. Cancer has found ways to evade the immune response; a pathway that can attenuate the innate immune response is via blocking immune checkpoints. Development of monoclonal antibodies against inhibitory immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have given rise to immunotherapy, which has shown remarkable responses in anti-tumor activity resulting in several U.S. Federal and Drug Administration (FDA)-approved checkpoint inhibitors. Various inflammatory markers and their prognostic and predictive implications in malignancies treated with immunotherapy will be discussed in this review.

Keywords:  CTLA-4 monoclonal antibodies; PD-1 inhibitors; PDL-1 inhibitors; immunotherapy; inflammation; lymphocyte-monocyte ratio; neutrophil-lymphocyte ratio; platelet-lymphocyte ratio

DOI:  https://doi.org/10.3390/biology10040325