Volume 4 (2020)

AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis

Zhen Cai1,#, Danni Peng1,# and Hui-Kuan Lin1

Although cancer metastasis represents the main cause for cancer-related death, the underlying mechanism involved in cancer metastasis remains largely unknown. The lack of the clear understanding of cancer metastasis has

A sympathetic gut connection drives the metabolic benefits of Roux-en-Y gastric bypass

Mohammed K. Hankir1

Surgery is regarded by many as the go-to treatment option for severe obesity; yet how physically altering the gastrointestinal tract produces such striking results on body weight and overall metabolic health is poorly understood. In a recent issue of Cell Reports Ye et al. (2020) compare mouse models of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), the two most commonly performed weight loss surgeries in the clinic today, to show that the former reconfiguring procedure selectively increases resting metabolic rate through splanchnic nerve-mediated browning of mesenteric white fat. More significantly, they demonstrate that this effect for RYGB is required for the maintained negative energy balance and improved glycemic control that it confers.

TLR4: the fall guy in sepsis?

Joseph Menassa1, Christina Nedeva1, Corey Pollock1 and Hamsa Puthalakath1

WHOLE GENOME CRISPR SCREEN AND THE IDENTIFICATION OF Treml4 We reasoned that if immune cells undergo apoptosis during sepsis, ablation of the gene responsible for this in a sub-population should

A mutant p53/Hif1α/miR-30d axis reprograms the secretory pathway promoting the release of a prometastatic secretome

Valeria Capaci1,2, Fiamma Mantovani1 and Giannino Del Sal1,2,3

– [table id=357/] MUT-p53 AS A DRIVER OF A MALIGNANT SECRETOME p53 mutants can promote tumorigenesis by affecting fundamental cellular pathways and functions, and by modulating the interplay of cancer

Targeting the TGFβ pathway in uterine carcinosarcoma

Shailendra Kumar Dhar Dwivedi1, Geeta Rao2, Anindya Dey1, Megan Buechel1, Yushan Zhang2, Min Zhang3, Da Yang3, Priyabrata Mukherjee2, Resham Bhattacharya1,4

Uterine carcinosarcoma (UCS) is a relatively infrequent, but extremely aggressive endometrial malignancy. Although surgery and chemotherapy have improved outcomes, overall survival (OS) remains dismal due to the lack of targeted therapy and biphasic (epithelial and mesenchymal) nature that renders the tumor aggressive and difficult to manage. Here we report a role of transforming growth factor-β (TGFβ) in maintaining epithelial to mesenchymal transition (EMT) phenotype and aggressiveness in UCS. Using a 3D-culture system, we evaluated the efficacy of the transforming growth factor-β receptor-I (TGFβR1) kinase inhibitor Galunisertib (GLT), alone and in combination with standard chemotherapeutic drugs used for the management of UCS. We demonstrate that GLT by inhibiting canonical and non-canonical signaling emanating from transforming growth factor-β1 (TGFβ1) reduces cellular viability, invasion, clonal growth and differentiation. (...)

Endocytosis in the adaptation to cellular stress

Tania López-Hernández1, Volker Haucke1,2 and Tanja Maritzen1

Cellular life is challenged by a multitude of stress conditions, triggered for example by alterations in osmolarity, oxygen or nutrient supply. Hence, cells have developed sophisticated stress responses to cope with these challenges. Some of these stress programs such as the heat shock response are understood in great detail, while other aspects remain largely elusive including potential stress-dependent adaptations of the plasma membrane proteome. The plasma membrane is not only the first point of encounter for many types of environmental stress, but given the diversity of receptor proteins and their associated molecules also represents the site at which many cellular signal cascades originate. Since these signaling pathways affect virtually all aspects of cellular life, changes in the plasma membrane proteome appear ideally suited to contribute to the cellular adaptation to stress. The most rapid means to alter the cell surface proteome in response to stress is by alterations in endocytosis. Changes in the overall endocytic flux or in the endocytic (...)

Exocytotic fusion pore under stress

Helena Haque Chowdhury1,2 and Robert Zorec1,2

Exocytosis is a universal process of eukaryotic cells, consisting of fusion between the vesicle and the plasma membranes, leading to the formation of a fusion pore, a channel through which vesicle cargo exits into the extracellular space. In 1986, Rand and Parsegian proposed several stages to explain the nature of membrane fusion. Following stimulation, it starts with focused stress destabilization of membranes in contact, followed by the coalescence of two membrane surfaces. In the next fraction of a millisecond, restabilization of fused membranes is considered to occur to maintain the cell's integrity. This view predicted that once a fusion pore is formed, it must widen abruptly, irreversibly and fully, whereby the vesicle membrane completely integrates with and collapses into the plasma membrane (full fusion exocytosis). However, recent experimental evidence has revealed that once the fusion pore opens, it may also reversibly close (transient or kiss-and-run exocytosis). Here, we present a historical perspective on understanding the mechanisms that initiate (...)

Targeting immune-checkpoint inhibitor resistance mechanisms by MEK inhibitor and agonist anti-CD40 antibody combination therapy

Daniel Baumann1,2 and Rienk Offringa1,2

– [table id=351/] IDENTIFYING SUITABLE CYTOSTATIC DRUGS FOR COMBINATORIAL IMMUNOTHERAPY The main dilemma in finding combinations of cytostatic and immunostimulatory drugs that act synergistically is as follows. On the one

Hyaluronan goes to great length

Vera Gorbunova1, Masaki Takasugi1 and Andrei Seluanov1

The naked mole rat is the longest-lived rodent with the maximum lifespan of over 35 years. Naked mole rats are protected from a wide range of age-related diseases including cancer,

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AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis

Zhen Cai1,#, Danni Peng1,# and Hui-Kuan Lin1

Although cancer metastasis represents the main cause for cancer-related death, the underlying mechanism involved in cancer metastasis remains largely unknown. The lack of the clear understanding of cancer metastasis has

A sympathetic gut connection drives the metabolic benefits of Roux-en-Y gastric bypass

Mohammed K. Hankir1

Surgery is regarded by many as the go-to treatment option for severe obesity; yet how physically altering the gastrointestinal tract produces such striking results on body weight and overall metabolic health is poorly understood. In a recent issue of Cell Reports Ye et al. (2020) compare mouse models of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), the two most commonly performed weight loss surgeries in the clinic today, to show that the former reconfiguring procedure selectively increases resting metabolic rate through splanchnic nerve-mediated browning of mesenteric white fat. More significantly, they demonstrate that this effect for RYGB is required for the maintained negative energy balance and improved glycemic control that it confers.

TLR4: the fall guy in sepsis?

Joseph Menassa1, Christina Nedeva1, Corey Pollock1 and Hamsa Puthalakath1

WHOLE GENOME CRISPR SCREEN AND THE IDENTIFICATION OF Treml4 We reasoned that if immune cells undergo apoptosis during sepsis, ablation of the gene responsible for this in a sub-population should

A mutant p53/Hif1α/miR-30d axis reprograms the secretory pathway promoting the release of a prometastatic secretome

Valeria Capaci1,2, Fiamma Mantovani1 and Giannino Del Sal1,2,3

– [table id=357/] MUT-p53 AS A DRIVER OF A MALIGNANT SECRETOME p53 mutants can promote tumorigenesis by affecting fundamental cellular pathways and functions, and by modulating the interplay of cancer

Targeting the TGFβ pathway in uterine carcinosarcoma

Shailendra Kumar Dhar Dwivedi1, Geeta Rao2, Anindya Dey1, Megan Buechel1, Yushan Zhang2, Min Zhang3, Da Yang3, Priyabrata Mukherjee2, Resham Bhattacharya1,4

Uterine carcinosarcoma (UCS) is a relatively infrequent, but extremely aggressive endometrial malignancy. Although surgery and chemotherapy have improved outcomes, overall survival (OS) remains dismal due to the lack of targeted therapy and biphasic (epithelial and mesenchymal) nature that renders the tumor aggressive and difficult to manage. Here we report a role of transforming growth factor-β (TGFβ) in maintaining epithelial to mesenchymal transition (EMT) phenotype and aggressiveness in UCS. Using a 3D-culture system, we evaluated the efficacy of the transforming growth factor-β receptor-I (TGFβR1) kinase inhibitor Galunisertib (GLT), alone and in combination with standard chemotherapeutic drugs used for the management of UCS. We demonstrate that GLT by inhibiting canonical and non-canonical signaling emanating from transforming growth factor-β1 (TGFβ1) reduces cellular viability, invasion, clonal growth and differentiation. (...)

Endocytosis in the adaptation to cellular stress

Tania López-Hernández1, Volker Haucke1,2 and Tanja Maritzen1

Cellular life is challenged by a multitude of stress conditions, triggered for example by alterations in osmolarity, oxygen or nutrient supply. Hence, cells have developed sophisticated stress responses to cope with these challenges. Some of these stress programs such as the heat shock response are understood in great detail, while other aspects remain largely elusive including potential stress-dependent adaptations of the plasma membrane proteome. The plasma membrane is not only the first point of encounter for many types of environmental stress, but given the diversity of receptor proteins and their associated molecules also represents the site at which many cellular signal cascades originate. Since these signaling pathways affect virtually all aspects of cellular life, changes in the plasma membrane proteome appear ideally suited to contribute to the cellular adaptation to stress. The most rapid means to alter the cell surface proteome in response to stress is by alterations in endocytosis. Changes in the overall endocytic flux or in the endocytic (...)

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Fine intercellular connections in development: TNTs, cytonemes, or intercellular bridges?

Olga Korenkova1,2, Anna Pepe1 and Chiara Zurzolo1

Intercellular communication is a fundamental property of multicellular organisms, necessary for their adequate responses to changing environment. Tunneling nanotubes (TNTs) represent a novel means of intercellular communication being a long cell-to-cell conduit. TNTs are actively formed under a broad range of stresses and are also proposed to exist under physiological conditions. Development is a physiological condition of particular interest, as it requires fine coordination. Here we discuss whether protrusions shown to exist during embryonic development of different species could be TNTs or if they represent other types of cell structure, like cytonemes or intercellular bridges, that are suggested to play an important role in development.

Kynurenine: an oncometabolite in colon cancer

Niranjan Venkateswaran1 and Maralice Conacci-Sorrell1,2,3

TRYPTOPHAN IS PREFERENTIALLY CONVERTED INTO KYNURENINE IN COLON CANCER Tryptophan can be utilized in three ways intracellularly: it can be incorporated into newly synthesized proteins, it can be processed by

Fatty acids – from energy substrates to key regulators of cell survival, proliferation and effector function

Danilo Cucchi1, Dolores Camacho-Muñoz2, Michelangelo Certo3, Valentina Pucino3, Anna Nicolaou2,4 and Claudio Mauro3,5,6

Recent advances in immunology and cancer research show that fatty acids, their metabolism and their sensing have a crucial role in the biology of many different cell types. Indeed, they are able to affect cellular behaviour with great implications for pathophysiology. Both the catabolic and anabolic pathways of fatty acids present us with a number of enzymes, receptors and agonists/antagonists that are potential therapeutic targets, some of which have already been successfully pursued. Fatty acids can affect the differentiation of immune cells, particularly T cells, as well as their activation and function, with important consequences for the balance between anti- and pro-inflammatory signals in immune diseases, such as rheumatoid arthritis, psoriasis, diabetes, obesity and cardiovascular conditions. In the context of cancer biology, fatty acids mainly provide substrates for (…)

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A sympathetic gut connection drives the metabolic benefits of Roux-en-Y gastric bypass

Mohammed K. Hankir1

Surgery is regarded by many as the go-to treatment option for severe obesity; yet how physically altering the gastrointestinal tract produces such striking results on body weight and overall metabolic health is poorly understood. In a recent issue of Cell Reports Ye et al. (2020) compare mouse models of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), the two most commonly performed weight loss surgeries in the clinic today, to show that the former reconfiguring procedure selectively increases resting metabolic rate through splanchnic nerve-mediated browning of mesenteric white fat. More significantly, they demonstrate that this effect for RYGB is required for the maintained negative energy balance and improved glycemic control that it confers.

Exploiting the circuit breaker cancer evolution model in human clear cell renal cell carcinoma

James J. Hsieh1 and Emily H. Cheng2,3,4

INTRODUCTION On average a human adult body encompasses fifty trillion cells (~5×1013) with a daily turnover of hundred billion cells (~1011) within which each contains two copies of ~three billion

HIF1α or mitophagy: which drives cardiomyocyte differentiation?

Beatriz Villarejo-Zori1,#, Juan Ignacio Jiménez-Loygorri1,# and Patricia Boya1

Cardiomyocytes (CMs) are the main cellular component of the heart's atria and ventricles, and their contractile capacity is the engine that drives blood flow throughout the body. The differentiation of

Copper – a novel stimulator of autophagy

Hans Zischka1,2 and Guido Kroemer3-7

In biomedicine, the transition metal copper has a Janus-faced dual role, as an essential but static cofactor of vital enzymes but also as a highly detrimental poison, if in excess.

Coronavirus infections: Epidemiological, clinical and immunological features and hypotheses

Didier Raoult1, Alimuddin Zumla2,3, Franco Locatelli4, Giuseppe Ippolito5 and Guido Kroemer6-10,*

INTRODUCTION Infections have been limiting quality of life and longevity throughout human history. Endemic infections have been associated to a significant number of avoidable deaths and a significant increase of

ACBP is an appetite stimulator across phylogenetic barriers

Frank Madeo1,2, Nektarios Tavernarakis3,4, José M. Bravo-San Pedro5-7,# and Guido Kroemer5-10,#

Human civilization is unique with respect to the organization of our natural environment, allowing constant supply of nutrients to most individuals in developed countries, contrasting with the natural fluctuation in

Necroptosis, tumor necrosis and tumorigenesis

Zheng-gang Liu1 and Delong Jiao1

INTRODUCTION Cell death can happen through either an active, regulated process, known as programmed cell death, or a passive, uncontrolled course. Because of the dramatic morphological differences of these two