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  • MinireviewDecember 31, 2022

    0 980 358

    Glyoxalase 1 as a Therapeutic Target in Cancer and Cancer Stem Cells

    Ji-Young Kim , Ji-Hye Jung , Seung-Joon Lee , Seon-Sook Han , and Seok-Ho Hong

    Mol. Cells 2022; 45(12): 869-876

    Abstract : Methylglyoxal (MG) is a dicarbonyl compound formed in cells mainly by the spontaneous degradation of the triose phosphate intermediates of glycolysis. MG is a powerful precursor of advanced glycation end products, which lead to strong dicarbonyl and oxidative stress. Although divergent functions of MG have been observed depending on its concentration, MG is considered to be a potential anti-tumor factor due to its cytotoxic effects within the oncologic domain. MG detoxification is carried out by the glyoxalase system. Glyoxalase 1 (Glo1), the ubiquitous glutathione-dependent enzyme responsible for MG degradation, is considered to be a tumor promoting factor due to it catalyzing the removal of cytotoxic MG. Indeed, various cancer types exhibit increased expression and activity of Glo1 that closely correlate with tumor cell growth and metastasis. Furthermore, mounting evidence suggests that Glo1 contributes to cancer stem cell survival. In this review, we discuss the role of Glo1 in the malignant progression of cancer and its possible use as a promising therapeutic target for tumor therapy. We also summarize therapeutic outcomes of Glo1 inhibitors as prospective treatments for the prevention of cancer.

  • MinireviewDecember 31, 2022

    0 704 179

    Advances in Optical Tools to Study Taste Sensation

    Gha Yeon Park , Hyeyeong Hwang , and Myunghwan Choi

    Mol. Cells 2022; 45(12): 877-882

    Abstract : Taste sensation is the process of converting chemical identities in food into a neural code of the brain. Taste information is initially formed in the taste buds on the tongue, travels through the afferent gustatory nerves to the sensory ganglion neurons, and finally reaches the multiple taste centers of the brain. In the taste field, optical tools to observe cellular-level functions play a pivotal role in understanding how taste information is processed along a pathway. In this review, we introduce recent advances in the optical tools used to study the taste transduction pathways.

  • Journal ClubDecember 31, 2022

    0 610 181

    How Does Global Warming Sabotage Plant Immunity?

    Souvik Dhar and Ji-Young Lee

    Mol. Cells 2022; 45(12): 883-885
  • Research ArticleDecember 31, 2022

    0 749 225

    RUNX1–Survivin Axis Is a Novel Therapeutic Target for Malignant Rhabdoid Tumors

    Masamitsu Mikami , Tatsuya Masuda, Takuya Kanatani, Mina Noura, Katsutsugu Umeda , Hidefumi Hiramatsu , Hirohito Kubota , Tomoo Daifu , Atsushi Iwai, Etsuko Yamamoto Hattori , Kana Furuichi, Saho Takasaki, Sunao Tanaka, Yasuzumi Matsui, Hidemasa Matsuo , Masahiro Hirata, Tatsuki R. Kataoka , Tatsutoshi Nakahata , Yasumichi Kuwahara , Tomoko Iehara, Hajime Hosoi, Yoichi Imai , Junko Takita , Hiroshi Sugiyama , Souichi Adachi , and Yasuhiko Kamikubo

    Mol. Cells 2022; 45(12): 886-895

    Abstract : Malignant rhabdoid tumor (MRT) is a highly aggressive pediatric malignancy with no effective therapy. Therefore, it is necessary to identify a target for the development of novel molecule-targeting therapeutic agents. In this study, we report the importance of the runt-related transcription factor 1 (RUNX1) and RUNX1–Baculoviral IAP (inhibitor of apoptosis) Repeat-Containing 5 (BIRC5/survivin) axis in the proliferation of MRT cells, as it can be used as an ideal target for anti-tumor strategies. The mechanism of this reaction can be explained by the interaction of RUNX1 with the RUNX1-binding DNA sequence located in the survivin promoter and its positive regulation. Specific knockdown of RUNX1 led to decreased expression of survivin, which subsequently suppressed the proliferation of MRT cells in vitro and in vivo. We also found that our novel RUNX inhibitor, Chb-M, which switches off RUNX1 using alkylating agent-conjugated pyrrole-imidazole polyamides designed to specifically bind to consensus RUNX-binding sequences (5′-TGTGGT-3′), inhibited survivin expression in vivo. Taken together, we identified a novel interaction between RUNX1 and survivin in MRT. Therefore the negative regulation of RUNX1 activity may be a novel strategy for MRT treatment.

  • Research ArticleDecember 31, 2022

    0 1156 420

    Temporal Transcriptome Analysis of SARS-CoV-2-Infected Lung and Spleen in Human ACE2-Transgenic Mice

    Jung Ah Kim , Sung-Hee Kim , Jung Seon Seo , Hyuna Noh , Haengdueng Jeong , Jiseon Kim , Donghun Jeon , Jeong Jin Kim , Dain On , Suhyeon Yoon , Sang Gyu Lee , Youn Woo Lee , Hui Jeong Jang , In Ho Park , Jooyeon Oh , Sang-Hyuk Seok , Yu Jin Lee , Seung-Min Hong , Se-Hee An , Joon-Yong Bae , Jung-ah Choi , Seo Yeon Kim , Young Been Kim , Ji-Yeon Hwang , Hyo-Jung Lee , Hong Bin Kim , Dae Gwin Jeong , Daesub Song , Manki Song , Man-Seong Park , Kang-Seuk Choi , Jun Won Park , Jun-Won Yun , Jeon-Soo Shin , Ho-Young Lee , Jun-Young Seo , Ki Taek Nam , Heon Yung Gee , and Je Kyung Seong

    Mol. Cells 2022; 45(12): 896-910

    Abstract : Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and potentially fatal virus. So far, most comprehensive analyses encompassing clinical and transcriptional manifestation have concentrated on the lungs. Here, we confirmed evident signs of viral infection in the lungs and spleen of SARS-CoV-2-infected K18-hACE2 mice, which replicate the phenotype and infection symptoms in hospitalized humans. Seven days post viral detection in organs, infected mice showed decreased vital signs, leading to death. Bronchopneumonia due to infiltration of leukocytes in the lungs and reduction in the spleen lymphocyte region were observed. Transcriptome profiling implicated the meticulous regulation of distress and recovery from cytokine-mediated immunity by distinct immune cell types in a time-dependent manner. In lungs, the chemokine-driven response to viral invasion was highly elevated at 2 days post infection (dpi). In late infection, diseased lungs, post the innate immune process, showed recovery signs. The spleen established an even more immediate line of defense than the lungs, and the cytokine expression profile dropped at 7 dpi. At 5 dpi, spleen samples diverged into two distinct groups with different transcriptome profile and pathophysiology. Inhibition of consecutive host cell viral entry and massive immunoglobulin production and proteolysis inhibition seemed that one group endeavored to survive, while the other group struggled with developmental regeneration against consistent viral intrusion through the replication cycle. Our results may contribute to improved understanding of the longitudinal response to viral infection and development of potential therapeutics for hospitalized patients affected by SARS-CoV-2.

  • Research ArticleDecember 31, 2022

    0 650 237

    Glycogen Synthase Kinase-3 Interaction Domain Enhances Phosphorylation of SARS-CoV-2 Nucleocapsid Protein

    Jun Seop Yun , Hyeeun Song , Nam Hee Kim , So Young Cha , Kyu Ho Hwang , Jae Eun Lee , Cheol-Hee Jeong , Sang Hyun Song , Seonghun Kim , Eunae Sandra Cho , Hyun Sil Kim , and Jong In Yook

    Mol. Cells 2022; 45(12): 911-922

    Abstract : A structural protein of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), nucleocapsid (N) protein is phosphorylated by glycogen synthase kinase (GSK)-3 on the serine/arginine (SR) rich motif located in disordered regions. Although phosphorylation by GSK-3β constitutes a critical event for viral replication, the molecular mechanism underlying N phosphorylation is not well understood. In this study, we found the putative alpha-helix L/FxxxL/AxxRL motif known as the GSK-3 interacting domain (GID), found in many endogenous GSK-3β binding proteins, such as Axins, FRATs, WWOX, and GSKIP. Indeed, N interacts with GSK-3β similarly to Axin, and Leu to Glu substitution of the GID abolished the interaction, with loss of N phosphorylation. The N phosphorylation is also required for its structural loading in a virus-like particle (VLP). Compared to other coronaviruses, N of Sarbecovirus lineage including bat RaTG13 harbors a CDK1-primed phosphorylation site and Gly-rich linker for enhanced phosphorylation by GSK-3β. Furthermore, we found that the S202R mutant found in Delta and R203K/G204R mutant found in the Omicron variant allow increased abundance and hyper-phosphorylation of N. Our observations suggest that GID and mutations for increased phosphorylation in N may have contributed to the evolution of variants.

  • Research ArticleDecember 31, 2022

    1 534 162

    The Aurora Kinase Inhibitor CYC116 Promotes the Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells

    Sijia Ji , Wanzhi Tu , Chenwen Huang , Ziyang Chen , Xinyue Ren , Bingqing He , Xiaoyan Ding , Yuelei Chen , and Xin Xie

    Mol. Cells 2022; 45(12): 923-934

    Abstract : Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have great potential in applications such as regenerative medicine, cardiac disease modeling, and in vitro drug evaluation. However, hPSC-CMs are immature, which limits their applications. During development, the maturation of CMs is accompanied by a decline in their proliferative capacity. This phenomenon suggests that regulating the cell cycle may facilitate the maturation of hPSC-CMs. Aurora kinases are essential kinases that regulate the cell cycle, the role of which is not well studied in hPSC-CM maturation. Here, we demonstrate that CYC116, an inhibitor of Aurora kinases, significantly promotes the maturation of CMs derived from both human embryonic stem cells (H1 and H9) and iPSCs (induced PSCs) (UC013), resulting in increased expression of genes related to cardiomyocyte function, better organization of the sarcomere, increased sarcomere length, increased number of mitochondria, and enhanced physiological function of the cells. In addition, a number of other Aurora kinase inhibitors have also been found to promote the maturation of hPSC-CMs. Our data suggest that blocking aurora kinase activity and regulating cell cycle progression may promote the maturation of hPSC-CMs.

  • Research ArticleDecember 31, 2022

    0 555 226

    Abstract : Liver cancer has a high prevalence, with majority of the cases presenting as hepatocellular carcinoma (HCC). The prognosis of metastatic HCC has hardly improved over the past decade, highlighting the necessity for liver cancer research. Studies have reported the ability of the KiSS1 gene to inhibit the growth or metastasis of liver cancer, but contradictory research results are also emerging. We, therefore, sought to investigate the effects of KiSS1 on growth and migration in human HCC cells. HepG2 human HCC cells were infected with lentivirus particles containing KiSS1. The overexpression of KiSS1 resulted in an increased proliferation rate of HCC cells. Quantitative polymerase chain reaction and immunoblotting revealed increased Akt activity, and downregulation of the G1/S phase cell cycle inhibitors. A significant increase in tumor spheroid formation with upregulation of β-catenin and CD133 was also observed. KiSS1 overexpression promoted the migratory, invasive ability, and metastatic capacity of the hepatocarcinoma cell line, and these effects were associated with changes in the expressions of epithelial mesenchymal transition (EMT)-related genes such as E-cadherin, N-cadherin, and slug. KiSS1 overexpression also resulted in dramatically increased tumor growth in the xenograft mouse model, and upregulation of proliferating cell nuclear antigen (PCNA) and Ki-67 in the HCC tumors. Furthermore, KiSS1 increased the angiogenic capacity by upregulation of the vascular endothelial growth factor A (VEGF-A) and CD31. Based on these observations, we infer that KiSS1 not only induces HCC proliferation, but also increases the metastatic potential by increasing the migratory ability and angiogenic capacity.

  • Research ArticleDecember 31, 2022

    0 679 200

    Increased Caveolin-2 Expression in Brain Endothelial Cells Promotes Age-Related Neuroinflammation

    Hyunju Park , Jung A Shin , Jiwoo Lim , Seulgi Lee , Jung-Hyuck Ahn , Jihee Lee Kang , and Youn-Hee Choi

    Mol. Cells 2022; 45(12): 950-962

    Abstract : Aging is a major risk factor for common neurodegenerative diseases. Although multiple molecular, cellular, structural, and functional changes occur in the brain during aging, the involvement of caveolin-2 (Cav-2) in brain ageing remains unknown. We investigated Cav-2 expression in brains of aged mice and its effects on endothelial cells. The human umbilical vein endothelial cells (HUVECs) showed decreased THP-1 adhesion and infiltration when treated with Cav-2 siRNA compared to control siRNA. In contrast, Cav-2 overexpression increased THP-1 adhesion and infiltration in HUVECs. Increased expression of Cav-2 and iba-1 was observed in brains of old mice. Moreover, there were fewer iba-1–positive cells in the brains of aged Cav-2 knockout (KO) mice than of wild-type aged mice. The levels of several chemokines were higher in brains of aged wild-type mice than in young wild-type mice; moreover, chemokine levels were significantly lower in brains of young mice as well as aged Cav-2 KO mice than in their wild-type counterparts. Expression of PECAM1 and VE-cadherin proteins increased in brains of old wild-type mice but was barely detected in brains of young wild-type and Cav-2 KO mice. Collectively, our results suggest that Cav-2 expression increases in the endothelial cells of aged brain, and promotes leukocyte infiltration and age-associated neuroinflammation.

  • Research ArticleDecember 31, 2022

    1 637 268

    SLC3A2 and SLC7A2 Mediate the Exogenous Putrescine-Induced Adipocyte Differentiation

    Jin Eom , Juhyun Choi , Sung-Suk Suh , and Jong Bae Seo

    Mol. Cells 2022; 45(12): 963-975

    Abstract : Exogenous polyamines are able to induce life span and improve glucose homeostasis and insulin sensitivity. However, the effects of exogenous polyamines on adipocyte differentiation and which polyamine transporters mediate them have not been elucidated yet. Here, we identified for the first time that exogenous polyamines can clearly stimulate adipocyte differentiation through polyamine transporters, solute carrier family 3 member A2 (SLC3A2) and SLC7A1. Exogenous polyamines markedly promote 3T3-L1 adipocyte differentiation by increasing the intracellular lipid accumulation and the expression of both adipogenic and lipogenic genes in a concentration-dependent manner. In particular, exogenous putrescine mainly regulates adipocyte differentiation in the early and intermediate stages. Moreover, we have assessed the expression of polyamine transporter genes in 3T3-L1 preadipocytes and adipocytes. Interestingly, the putrescine-induced adipocyte differentiation was found to be significantly suppressed in response to a treatment with a polyamine transporter inhibitor (AMXT-1501). Furthermore, knockdown experiments using siRNA that specifically targeted SLC3A2 or SLC7A2, revealed that both SLC3A2 and SLC7A2 act as important transporters in the cellular importing of exogenous putrescine. Thus, the exogenous putrescine entering the adipocytes via cellular transporters is involved in adipogenesis through a modulation of both the mitotic clonal expansion and the expression of master transcription factors. Taken together, these results suggest that exogenous polyamines (such as putrescine) entering the adipocytes through polyamine transporters, can stimulate adipogenesis.

Mol. Cells
Sep 30, 2023 Vol.46 No.9, pp. 527~572
Chronic obstructive pulmonary disease (COPD) is marked by airspace enlargement (emphysema) and small airway fibrosis, leading to airflow obstruction and eventual respiratory failure. Shown is a microphotograph of hematoxylin and eosin (H&E)-stained histological sections of the enlarged alveoli as an indicator of emphysema. Piao et al. (pp. 558-572) demonstrate that recombinant human hyaluronan and proteoglycan link protein 1 (rhHAPLN1) significantly reduces the extended airspaces of the emphysematous alveoli by increasing the levels of TGF-β receptor I and SIRT1/6, as a previously unrecognized mechanism in human alveolar epithelial cells, and consequently mitigates COPD.


Molecules and Cells

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