• 생명과학회지
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• 제34권10호
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• pp.744-754
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• 2024

암세포는 통제되지 않는 세포분열 과정 중, 생체 에너지와 생합성 중간체를 제공하기 위하여 정상세포와는 현저히 다른 독특한 대사과정을 나타낸다. 포도당으로부터 생성된 pyruvate의 대부분을 lactate로 전환하여 비효율적으로 ATP 생성하는 호기적 해당작용(Warburg effect)으로 glutamine 대사를 통해 부족한 에너지를 해결하고 있다. Glutamine은 혈액과 근육에서 가장 풍부한 아미노산으로서, glutaminolysis를 통해 TCA cycle을 통한 생체 에너지, 지질과 대사산물의 합성뿐만 아니라 아미노산과 뉴클레오티드 합성에 사용된다. 암세포가 정상세포보다 glutamine에 의존하여 TCA cycle 대사산물의 절반 이상이 glutamine에서 파생되는 glutamine 중독 현상을 나타낸다. 종양유전자 c-Myc는 glutamine 대사에 관련된 glutamine 대사 유전자의 발현을 조절하고, glutamine의 흡수를 촉진한다. Glutaminase가 종양을 유발하거나 종양을 억제하는지는 isoenzymes의 관점에서 논란의 여지가 있으나 GLS1은 발암 가능성이 더 높아 유망한 치료 대상인 반면에 GLS2는 종양 저해제로서 작용하는 것으로 알려졌다. 암 대사체의 복잡하고 정교한 네트워크에 기반한 4세대 대사항암제는 암세포의 에너지 대사를 직접 제어하여 영양 공급을 차단해 부작용 없이 항암효과를 극대화하는 요법으로 2010년대 중반 이후 연구가 활발히 진행되고 있다. Glutaminolysis에서 glutaminase는 초기 단계를 촉매하는 효소로서 암 대사 및 종양 진행에 매우 중요하여 glutaminase 효소를 약물 표적화하는 새로운 기전의 항암제 개발이 유망한 전략으로 떠오르고 있다.

• KSBB Journal
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• 제13권3호
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• pp.289-294
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• 1998

The effects of various step-fortifications of the initial medium with amino acids, glucose, and vitamines on the growth and metabolism of a hybridoma cell line in batch cultures were quantified. Comparisons between the metabolic rates of the various cultivations were made for the exponential growth phase. Fortification of the basal medium resulted in higher cell densities through a prolonged growth phase, but the maximum specific growth rate was not affected. The uptake rate of glutamine increased with the addition of amino acids but did not change upon the addition of glucose or vitamines. The specific glucose consumption decreased slightly with the addition of amino acids but increased production of lactate and {{{{ { NH}`_{4 } ^{ +} }}}}. A reciprocal relationship between the yields of {{{{ { NH}`_{4 } ^{+ } }}}} and lactate indicated a joint regulation of glycolysis and glutaminolysis.

• Toxicological Research
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• 제31권4호
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• pp.323-330
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• 2015

Cancer is a disease characterized by uncontrolled growth. Metabolic demands to sustain rapid proliferation must be compelling since aerobic glycolysis is the first as well as the most commonly shared characteristic of cancer. During the last decade, the significance of metabolic reprogramming of cancer has been at the center of attention. Nonetheless, despite all the knowledge gained on cancer biology, the field is not able to reach agreement on the issue of mitochondria: Are damaged mitochondria the cause for aerobic glycolysis in cancer? Warburg proposed the damaged mitochondria theory over 80 years ago; the field has been testing the theory equally long. In this review, we will discuss alterations in metabolic fluxes of cancer cells, and provide an opinion on the damaged mitochondria theory.

• Molecules and Cells
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• 제39권12호
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• pp.847-854
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• 2016

The early landmark discoveries in cancer metabolism research have uncovered metabolic processes that support rapid proliferation, such as aerobic glycolysis (Warburg effect), glutaminolysis, and increased nucleotide biosynthesis. However, there are limitations to the effectiveness of specifically targeting the metabolic processes which support rapid proliferation. First, as other normal proliferative tissues also share similar metabolic features, they may also be affected by such treatments. Secondly, targeting proliferative metabolism may only target the highly proliferating "bulk tumor" cells and not the slowergrowing, clinically relevant cancer stem cell subpopulations which may be required for an effective cure. An emerging body of research indicates that altered metabolism plays key roles in supporting proliferation-independent functions of cancer such as cell survival within the ischemic and acidic tumor microenvironment, immune system evasion, and maintenance of the cancer stem cell state. As these aspects of cancer cell metabolism are critical for tumor maintenance yet are less likely to be relevant in normal cells, they represent attractive targets for cancer therapy.

• Journal of Microbiology and Biotechnology
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• 제33권1호
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• pp.114-122
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• 2023

A family of signal transduction pathways known as wingless type (Wnt) signaling pathways is essential to developmental processes like cell division and proliferation. Mutation in Wnt signaling results in a variety of diseases, including cancers of the breast, colon, and skin, metabolic disease, and neurodegenerative disease; thus, the Wnt signaling pathways have been attractive targets for disease treatment. However, the complicatedness and large involveness of the pathway often hampers pinpointing the specific targets of the metabolic process. In our current study, we investigated the differential metabolic regulation by the overexpression of the Wnt signaling pathway in a timely-resolved manner by applying high-throughput and un-targeted metabolite profiling. We have detected and annotated 321 metabolite peaks from a total of 36 human embryonic kidney (HEK) 293 cells using GC-TOF MS and LC-Orbitrap MS. The un-targeted metabolomic analysis identified the radical reprogramming of a range of central carbon/nitrogen metabolism pathways, including glycolysis, TCA cycle, and glutaminolysis, and fatty acid pathways. The investigation, combined with targeted mRNA profiles, elucidated an explicit understanding of activated fatty acid metabolism (β-oxidation and biosynthesis). The findings proposed detailed mechanistic biochemical dynamics in response to Wnt-driven metabolic changes, which may help design precise therapeutic targets for Wnt-related diseases.

• BMB Reports
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• 제51권9호
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• pp.474-479
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• 2018

Cisplatin is one of the most effective chemotherapeutic drugs used in the treatment of HCC, but many patients will ultimately relapse with cisplatin-resistant disease. Used in combination with cisplatin, resveratrol has synergistic effect of increasing chemosensitivity of cisplatin in various cancer cells. However, the mechanisms of resveratrol enhancing cisplatin-induced toxicity have not been well characterized. Our study showed that resveratrol enhances cisplatin toxicity in human hepatoma cells via an apoptosis-dependent mechanism. Further studies reveal that resveratrol decreases the absorption of glutamine and glutathione content by reducing the expression of glutamine transporter ASCT2. Flow cytometric analyses demonstrate that resveratrol and cisplatin combined treatment leads to a significant increase in ROS production compared to resveratrol or cisplatin treated hepatoma cells alone. Phosphorylated H2AX (${\gamma}H2AX$) foci assay demonstrate that both resveratrol and cisplatin treatment result in a significant increase of ${\gamma}H2AX$ foci in hepatoma cells, and the resveratrol and cisplatin combined treatment results in much more ${\gamma}H2AX$ foci formation than either resveratrol or cisplatin treatment alone. Furthermore, our studies show that over-expression of ASCT2 can attenuate cisplatin-induced ROS production, ${\gamma}H2AX$ foci formation and apoptosis in human hepatoma cells. Collectively, our studies suggest resveratrol may sensitize human hepatoma cells to cisplatin chemotherapy via gluta${\gamma}H2AX$mine metabolism inhibition.

• Journal of Microbiology and Biotechnology
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• 제23권11호
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• pp.1586-1597
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• 2013

Energy-efficient metabolic responses were often noted in high-productive cultures. To better understand these metabolic responses, an investigation into the relationship between metabolic responses and energy regulation was conducted via a comparative analysis among cultures with different energy source supplies. Both glycolysis and glutaminolysis were studied through the kinetic analyses of major extracellular metabolites concerning the fast and slow cell growth stages, respectively, as well as the time-course profiles of intracellular metabolites. In three cultures showing distinct antibody productivities, the amino acid metabolism and energy state were further examined. Both the transition of lactate from production to consumption and steady intracellular pools of pyruvate and lactate were observed to be correlated with efficient energy regulation. In addition, an efficient utilization of amino acids as the replenishment for the TCA cycle was also found in the cultures with upregulated energy metabolism. It was further revealed that the inefficient energy regulation would cause low cell productivity based on the comparative analysis of cell growth and productivity in cultures having distinct energy regulation.