bims-almceb 2021-01-10 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021–01–10
ten papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Targeting mitochondrial ion channels for cancer therapy.
NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity.
Development of Philadelphia chromosome-negative acute myeloid leukemia with IDH2 and NPM1 mutations in a patient with chronic myeloid leukemia who showed a major molecular response to tyrosine kinase inhibitor therapy.
Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview.
SIRT3-Mediated SOD2 and PGC-1α Contribute to Chemoresistance in Colorectal Cancer Cells.
Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo.
Preclinical development of CD126 CAR-T cells with broad antitumor activity.
Cancer Stemness Meets Immunity: From Mechanism to Therapy.
Melatonin synthesis in and uptake by mitochondria: implications for diseased cells with dysfunctional mitochondria.
Metabolic-targeted Combination Therapy With Dichloroacetate and Metformin Suppresses Glioblastoma Cell Line Growth In Vitro and In Vivo.

Redox Biol. 2020 Dec 24. pii: S2213-2317(20)31051-X. [Epub ahead of print] 101846

Targeting mitochondrial ion channels for cancer therapy.

Ildiko Szabo, Mario Zoratti, Lucia Biasutto.

  Pharmacological targeting of mitochondrial ion channels is emerging as a promising approach to eliminate cancer cells; as most of these channels are differentially expressed and/or regulated in cancer cells in comparison to healthy ones, this strategy may selectively eliminate the former. Perturbation of ion fluxes across the outer and inner membranes is linked to alterations of redox state, membrane potential and bioenergetic efficiency. This leads to indirect modulation of oxidative phosphorylation, which is/may be fundamental for both cancer and cancer stem cell survival. Furthermore, given the crucial contribution of mitochondria to intrinsic apoptosis, modulation of their ion channels leading to cytochrome c release may be of great advantage in case of resistance to drugs triggering apoptotic events upstream of the mitochondrial phase. In the present review, we give an overview of the known mitochondrial ion channels and of their modulators capable of killing cancer cells. In addition, we discuss state-of-the-art strategies using mitochondriotropic drugs or peptide-based approaches allowing a more efficient and selective targeting of mitochondrial ion channel-linked events.

Keywords:  Cancer; Channel interactions; Drug targeting; Ion channels; Mitochondria

DOI:  https://doi.org/10.1016/j.redox.2020.101846
Nat Immunol. 2021 Jan 04.

NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity.

Meidi Gu, Xiaofei Zhou, Jee Hyung Sohn, Lele Zhu, Zuliang Jie, Jin-Young Yang, Xiaofeng Zheng, Xiaoping Xie, Jie Yang, Yaoyao Shi, Hans D Brightbill, Jae Bum Kim, Jing Wang, Xuhong Cheng, Shao-Cong Sun.

Metabolic reprograming toward aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show that deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8+ effector T cells hypofunctional in the tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8+ T cell metabolism and effector function, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. NIK regulates T cell metabolism via a NF-κB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK prevents autophagic degradation of HK2 through controlling cellular reactive oxygen species levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that mediates production of the antioxidant NADPH. We show that the G6PD-NADPH redox system is important for HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a post-translational mechanism of metabolic regulation.

DOI: https://doi.org/10.1038/s41590-020-00829-6
Int J Hematol. 2021 Jan 05.

Development of Philadelphia chromosome-negative acute myeloid leukemia with IDH2 and NPM1 mutations in a patient with chronic myeloid leukemia who showed a major molecular response to tyrosine kinase inhibitor therapy.

Fumi Nakamura, Honoka Arai, Yasuhito Nannya, Motoshi Ichikawa, Shiho Furuichi, Fusako Nagasawa, Wataru Takahashi, Tomoyuki Handa, Yuko Nakamura, Hiroko Tanaka, Yuka Nakamura, Ko Sasaki, Satoru Miyano, Seishi Ogawa, Kinuko Mitani.

  Tyrosine kinase inhibitors (TKIs) are standard therapies for chronic myeloid leukemia (CML) that can eradicate Ph-positive leukemic cells. However, disease control is not achievable in a minority of cases, most commonly due to evolution of TKI-resistant clones. There have also been rare cases of emergence of Ph-negative clones with other cytogenetic abnormalities, and, less commonly, development of Ph-negative acute myeloid leukemia (AML), whose molecular pathogenesis is largely unknown. Here we report molecular features of a patient with Ph + CML who developed Ph-negative AML after showing a major molecular response to dasatinib. A 55-year-old man was diagnosed with CML. He achieved a complete cytogenetic response three months after dasatinib therapy but developed AML with normal karyotype 1 year later. After receiving induction and consolidation chemotherapy for AML, the patient achieved complete remission with no evidence of CML under maintenance with bosutinib. Targeted sequencing of serial bone marrow samples identified mutations in IDH2 and NPM1 in the Ph-negative AML cells, which had not been detected in CML cells. These results suggest that Ph-negative AML in this patient originated from a preleukemic population, which might have expanded during or after the successful elimination of CML clones with TKI therapy.

Keywords:  Chronic myeloid leukemia; Ph-negative acute myeloid leukemia; Targeted sequencing; Tyrosine kinase inhibitor

DOI:  https://doi.org/10.1007/s12185-020-03074-7
Front Oncol. 2020 ;10 604143

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview.

Alessandro Barbato, Grazia Scandura, Fabrizio Puglisi, Daniela Cambria, Enrico La Spina, Giuseppe Alberto Palumbo, Giacomo Lazzarino, Daniele Tibullo, Francesco Di Raimondo, Cesarina Giallongo, Alessandra Romano.

  The combined derangements in mitochondria network, function and dynamics can affect metabolism and ATP production, redox homeostasis and apoptosis triggering, contributing to cancer development in many different complex ways. In hematological malignancies, there is a strong relationship between cellular metabolism, mitochondrial bioenergetics, interconnections with supportive microenvironment and drug resistance. Lymphoma and chronic lymphocytic leukemia cells, e.g., adapt to intrinsic oxidative stress by increasing mitochondrial biogenesis. In other hematological disorders such as myeloma, on the contrary, bioenergetics changes, associated to increased mitochondrial fitness, derive from the adaptive response to drug-induced stress. In the bone marrow niche, a reverse Warburg effect has been recently described, consisting in metabolic changes occurring in stromal cells in the attempt to metabolically support adjacent cancer cells. Moreover, a physiological dynamic, based on mitochondria transfer, between tumor cells and their supporting stromal microenvironment has been described to sustain oxidative stress associated to proteostasis maintenance in multiple myeloma and leukemia. Increased mitochondrial biogenesis of tumor cells associated to acquisition of new mitochondria transferred by mesenchymal stromal cells results in augmented ATP production through increased oxidative phosphorylation (OX-PHOS), higher drug resistance, and resurgence after treatment. Accordingly, targeting mitochondrial biogenesis, electron transfer, mitochondrial DNA replication, or mitochondrial fatty acid transport increases therapy efficacy. In this review, we summarize selected examples of the mitochondrial derangements in hematological malignancies, which provide metabolic adaptation and apoptosis resistance, also supported by the crosstalk with tumor microenvironment. This field promises a rational design to improve target-therapy including the metabolic phenotype.

Keywords:  OX-PHOS; acute myeloid leukemia; chronic lymphatic leukemia; lymphoma; mitochondria; multiple myeloma

DOI:  https://doi.org/10.3389/fonc.2020.604143
Ann Surg Oncol. 2021 Jan 03.

SIRT3-Mediated SOD2 and PGC-1α Contribute to Chemoresistance in Colorectal Cancer Cells.

Masakatsu Paku, Naotsugu Haraguchi, Mitsunobu Takeda, Shiki Fujino, Takayuki Ogino, Hidekazu Takahashi, Norikatsu Miyoshi, Mamoru Uemura, Tunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Hidetoshi Eguchi.

BACKGROUND: Anticancer drugs generate excessive reactive oxygen species (ROS), which can cause cell death. Cancer cells can resist this oxidative stress, but the mechanism of resistance and associations with chemoresistance are unclear. Here, we focused on Sirtuin 3 (SIRT3), a deacetylating mitochondrial enzyme, in oxidative stress resistance in colorectal cancer (CRC).
METHODS: To evaluate SIRT3-related changes in mitochondrial function, ROS (mtROS) induction, and apoptosis, we used the human CRC cell lines HT29 and HCT116 transfected with short-hairpin RNA targeting SIRT3 and small interfering RNAs targeting superoxide dismutase 2 mitochondrial (SOD2) and peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α). In 142 clinical specimens from patients with CRC, we also assessed the association of SIRT3 protein levels (high/low) and prognosis.
RESULTS: SIRT3 expression correlated with mtROS generation and apoptosis induction in cells treated with anticancer agents. Suppressing SIRT3 increased mtROS levels and cell sensitivity to anticancer agents. SIRT3 knockdown decreased SOD2 expression and activity, and suppressing SOD2 also improved sensitivity to anticancer drugs. In addition, SIRT3 was recruited with PGC-1α under oxidative stress, and suppressing SIRT3 decreased PGC-1α expression and mitochondrial function. PGC-1α knockdown decreased mitochondrial activity and increased apoptosis in cells treated with anticancer drugs. In resected CRC specimens, high vs low SIRT3 protein levels were associated with significantly reduced cancer-specific survival.
CONCLUSIONS: SIRT3 expression affected CRC cell chemoresistance through SOD2 and PGC-1α regulation and was an independent prognostic factor in CRC. SIRT3 may be a novel target for CRC therapies and a predictive marker of sensitivity to chemotherapy.

DOI: https://doi.org/10.1245/s10434-020-09373-x
Materials (Basel). 2021 Jan 04. pii: E208. [Epub ahead of print]14(1):

Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo.

Hai Thanh Pham, Mitsuaki Ono, Emilio Satoshi Hara, Ha Thi Thu Nguyen, Anh Tuan Dang, Hang Thuy Do, Taishi Komori, Ikue Tosa, Yuri Hazehara-Kunitomo, Yuya Yoshioka, Yasutaka Oida, Kentaro Akiyama, Takuo Kuboki.

  Aging tissues present a progressive decline in homeostasis and regenerative capacities, which has been associated with degenerative changes in tissue-specific stem cells and stem cell niches. We hypothesized that amino acids could regulate the stem cell phenotype and differentiation ability of human bone marrow-derived mesenchymal stromal cells (hBMSCs). Thus, we performed a screening of 22 standard amino acids and found that D-tryptophan (10 μM) increased the number of cells positive for the early stem cell marker SSEA-4, and the gene expression levels of OCT-4, NANOG, and SOX-2 in hBMSCs. Comparison between D- and L-tryptophan isomers showed that the latter presents a stronger effect in inducing the mRNA levels of Oct-4 and Nanog, and in increasing the osteogenic differentiation of hBMSCs. On the other hand, L-tryptophan suppressed adipogenesis. The migration and colony-forming ability of hBMSCs were also enhanced by L-tryptophan treatment. In vivo experiments delivering L-tryptophan (50 mg/kg/day) by intraperitoneal injections for three weeks confirmed that L-tryptophan significantly increased the percentage of cells positive for SSEA-4, mRNA levels of Nanog and Oct-4, and the migration and colony-forming ability of mouse BMSCs. L-kynurenine, a major metabolite of L-tryptophan, also induced similar effects of L-tryptophan in enhancing stemness and osteogenic differentiation of BMSCs in vitro and in vivo, possibly indicating the involvement of the kynurenine pathway as the downstream signaling of L-tryptophan. Finally, since BMSCs migrate to the wound healing site to promote bone healing, surgical defects of 1 mm in diameter were created in mouse femur to evaluate bone formation after two weeks of L-tryptophan or L-kynurenine injection. Both L-tryptophan and L-kynurenine accelerated bone healing compared to the PBS-injected control group. In summary, L-tryptophan enhanced the stemness and osteoblastic differentiation of BMSCs and may be used as an essential factor to maintain the stem cell properties and accelerate bone healing and/or prevent bone loss.

Keywords:  adipogenesis; amino acid; anabolics; injury/fracture healing; kynurenine; mesenchymal stromal cells; osteogenesis; screening; stemness; tryptophan

DOI:  https://doi.org/10.3390/ma14010208
Blood Cancer J. 2021 Jan 04. 11(1): 3

Preclinical development of CD126 CAR-T cells with broad antitumor activity.

Ameet K Mishra, Iris Kemler, David Dingli.

Chimeric antigen receptor T (CAR-T) cell therapy is a transformative approach to cancer eradication. CAR-T is expensive partly due to the restricted use of each CAR construct for specific tumors. Thus, a CAR construct with broad antitumor activity can be advantageous. We identified that CD126 is expressed by many hematologic and solid tumors, including multiple myeloma, lymphoma, acute myeloid leukemia, pancreatic and prostate adenocarcinoma, non-small cell lung cancer, and malignant melanoma among others. CAR-T cells targeting CD126 were generated and shown to kill many tumor cells in an antigen-specific manner and with efficiency directly proportional to CD126 expression. Soluble CD126 did not interfere with CAR-T cell killing. The CAR-T constructs bind murine CD126 but caused no weight loss or hepatotoxicity in mice. In multiple myeloma and prostate adenocarcinoma xenograft models, intravenously injected CD126 CAR-T cells infiltrated within, expanded, and killed tumor cells without toxicity. Binding of soluble interleukin-6 receptor (sIL-6R) by CAR-T cells could mitigate cytokine release syndrome. Murine SAA-3 levels were lower in mice injected with CD126 CAR-T compared to controls, suggesting that binding of sIL-6R by CAR-T cells could mitigate cytokine release syndrome. CD126 provides a novel therapeutic target for CAR-T cells for many tumors with a low risk of toxicity.

DOI: https://doi.org/10.1038/s41408-020-00405-z
Cell Rep. 2021 Jan 05. pii: S2211-1247(20)31586-2. [Epub ahead of print]34(1): 108597

Cancer Stemness Meets Immunity: From Mechanism to Therapy.

Peiwen Chen, Wen-Hao Hsu, Jincheng Han, Yan Xia, Ronald A DePinho.

  Cancer stem cells (CSCs) are self-renewing cells that facilitate tumor initiation, promote metastasis, and enhance cancer therapy resistance. Transcriptomic analyses across many cancer types have revealed a prominent association between stemness and immune signatures, potentially implying a biological interaction between such hallmark features of cancer. Emerging experimental evidence has substantiated the influence of CSCs on immune cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and T cells, in the tumor microenvironment and, reciprocally, the importance of such immune cells in sustaining CSC stemness and its survival niche. This review covers the cellular and molecular mechanisms underlying the symbiotic interactions between CSCs and immune cells and how such heterotypic signaling maintains a tumor-promoting ecosystem and informs therapeutic strategies intercepting this co-dependency.

Keywords:  T cells; cancer stem cell; immunity; immunotherapy; myeloid-derived suppressor cells; stemness; symbiotic interaction; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.celrep.2020.108597
Future Med Chem. 2021 Jan 05.

Melatonin synthesis in and uptake by mitochondria: implications for diseased cells with dysfunctional mitochondria.

Russel J Reiter, Ramaswamy Sharma, Debora Aparecida Pires de Campos Zuccari, Luiz Gustavo de Almeida Chuffa, Walter Manucha, Carmen Rodriguez.



Keywords:  Warburg effect; aerobic glycolysis; glycolytics; hypoxia-inducible factor 1α; oxidative phosphorylation; pyruvate dehydrogenase; reactive oxygen species; superoxide dismutase 2; zygote

DOI:  https://doi.org/10.4155/fmc-2020-0326
In Vivo. 2021 Jan-Feb;35(1):35(1): 341-348

Metabolic-targeted Combination Therapy With Dichloroacetate and Metformin Suppresses Glioblastoma Cell Line Growth In Vitro and In Vivo.

Laura Korsakova, Jan Aleksander Krasko, Edgaras Stankevicius.

   BACKGROUND/AIM: We investigated the hypothesis that dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, and metformin (MET), an antidiabetic agent and complex I inhibitor, have synergistic cytotoxic effects in glioblastoma cells in vitro and in vivo.
MATERIALS AND METHODS: We performed dose response experiments and combination index calculation. Apoptotic and necrotic cells were estimated by flow cytometry. Cell metabolism was evaluated by Seahorse analysis and lactate export. Overall survival and tumor volume growth experiments were performed in C57BL/6 mice GL-261 allograft model.
RESULTS: DCA and MET showed dose-dependent cytotoxicity and synergistic effects. DCA alleviated the increase in lactate production induced by MET. Seahorse analysis showed that DCA treatment results in increased oxygen consumption rate, which is decreased by MET. DCA and MET significantly inhibited tumor growth and increased overall survival in mice.
CONCLUSION: Compounds targeting tumor cell metabolism could become potential treatment options for glioblastoma multiforme.

Keywords:  Dichloroacetate; Warburg effect; glioblastoma; metformin

DOI:  https://doi.org/10.21873/invivo.12265