Association of mitochondrial homeostasis and dynamic balance with malignant biological behaviors of gastrointestinal cancer

Liu, Ao-Ran; Lv, Zhi; Yan, Ziwei; Wu, Xiaoyang; Yan, Li-rong; Sun, Liping; Yuan, Yuan; Xu, Qinying

doi:10.1186/s12967-023-03878-1

Cited by 11 publications

(6 citation statements)

References 132 publications

(88 reference statements)

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“…Metabolic changes often reflect changes in the mitochondrial dynamics and functionality caused by changes in the cell cytoskeleton [ 93 , 94 ]. We addressed this by assessing the levels of the expression in Ca Ski subclones of A-tubulin as the parameter reflecting the state of microtubules (MT) and of Y-tubulin as the parameter reflecting the condition of the MT-supported mitochondrial network [ 95 ].…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Reverse Transcriptase Expression in HPV16-Infected Epidermoid Carcinoma Cells Alters E6 Expression and Cellular Metabolism, and Induces a Hybrid Epithelial/Mesenchymal Cell Phenotype

Zhitkevich,

Bayurova,

Avdoshina

et al. 2024

Viruses

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The high incidence of epithelial malignancies in HIV-1 infected individuals is associated with co-infection with oncogenic viruses, such as high-risk human papillomaviruses (HR HPVs), mostly HPV16. The molecular mechanisms underlying the HIV-1-associated increase in epithelial malignancies are not fully understood. A collaboration between HIV-1 and HR HPVs in the malignant transformation of epithelial cells has long been anticipated. Here, we delineated the effects of HIV-1 reverse transcriptase on the in vitro and in vivo properties of HPV16-infected cervical cancer cells. A human cervical carcinoma cell line infected with HPV16 (Ca Ski) was made to express HIV-1 reverse transcriptase (RT) by lentiviral transduction. The levels of the mRNA of the E6 isoforms and of the factors characteristic to the epithelial/mesenchymal transition were assessed by real-time RT-PCR. The parameters of glycolysis and mitochondrial respiration were determined using Seahorse technology. RT expressing Ca Ski subclones were assessed for the capacity to form tumors in nude mice. RT expression increased the expression of the E6*I isoform, modulated the expression of E-CADHERIN and VIMENTIN, indicating the presence of a hybrid epithelial/mesenchymal phenotype, enhanced glycolysis, and inhibited mitochondrial respiration. In addition, the expression of RT induced phenotypic alterations impacting cell motility, clonogenic activity, and the capacity of Ca Ski cells to form tumors in nude mice. These findings suggest that HIV-RT, a multifunctional protein, affects HPV16-induced oncogenesis, which is achieved through modulation of the expression of the E6 oncoprotein. These results highlight a complex interplay between HIV antigens and HPV oncoproteins potentiating the malignant transformation of epithelial cells.

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Section: Discussionmentioning

confidence: 99%

HIV-1 Reverse Transcriptase Expression in HPV16-Infected Epidermoid Carcinoma Cells Alters E6 Expression and Cellular Metabolism, and Induces a Hybrid Epithelial/Mesenchymal Cell Phenotype

Zhitkevich,

Bayurova,

Avdoshina

et al. 2024

Viruses

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“…Tumors can also derange the mitochondrial dynamics rheostat to gain proliferative and survival advantages. Accordingly, Drp1-dependent increased mitochondrial fission has been reported in several solid [ 10 – 14 ] and haematological malignancies, including MM [ 15 , 16 ], overall contributing to metabolic reprogramming, cell death evasion, migration and invasiveness of tumor cells. On this basis, the selective antagonism of mitochondrial fission via Drp1 targeting might represent a promising therapeutic approach for cancer, and Drp1 synthetic inhibitors have proven effective in reducing proliferation and inducing apoptosis in cancer cells, both in vitro and in vivo [ 61 , 62 ].…”

Section: Discussionmentioning

confidence: 99%

“…Drp1 phosphorylation at S616, mediated by protein kinases as ERK2, CDK1, p38-MAPK and many others, enhances its translocation to the outer mitochondrial membrane and increases its fission-promoting activity [ 9 ]. Elevated mitochondrial fission, caused by increased expression and/or activity of Drp1, in turn drives metabolic reprogramming, cell cycle progression and cell death evasion, enhancing migration and invasiveness in a wide variety of solid cancers [ 10 – 14 ]. Defects in mitochondrial dynamics have been also reported in hematological malignancies, as T-cell acute lymphoblastic leukemia and MM [ 15 , 16 ], which enhance the expression and/or activity of fission proteins, like Drp1, to promote survival and resistance to chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Targeting of mitochondrial fission through natural flavanones elicits anti-myeloma activity

Torcasio,

Gallo Cantafio,

Veneziano

et al. 2024

J Transl Med

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Background Mitochondrial alterations, often dependent on unbalanced mitochondrial dynamics, feature in the pathobiology of human cancers, including multiple myeloma (MM). Flavanones are natural flavonoids endowed with mitochondrial targeting activities. Herein, we investigated the capability of Hesperetin (Hes) and Naringenin (Nar), two aglycones of Hesperidin and Naringin flavanone glycosides, to selectively target Drp1, a pivotal regulator of mitochondrial dynamics, prompting anti-MM activity. Methods Molecular docking analyses were performed on the crystallographic structure of Dynamin-1-like protein (Drp1), using Hes and Nar molecular structures. Cell viability and apoptosis were assessed in MM cell lines, or in co-culture systems with primary bone marrow stromal cells, using Cell Titer Glo and Annexin V-7AAD staining, respectively; clonogenicity was determined using methylcellulose colony assays. Transcriptomic analyses were carried out using the Ion AmpliSeq™ platform; mRNA and protein expression levels were determined by quantitative RT-PCR and western blotting, respectively. Mitochondrial architecture was assessed by transmission electron microscopy. Real time measurement of oxygen consumption was performed by high resolution respirometry in living cells. In vivo anti-tumor activity was evaluated in NOD-SCID mice subcutaneously engrafted with MM cells. Results Hes and Nar were found to accommodate within the GTPase binding site of Drp1, and to inhibit Drp1 expression and activity, leading to hyperfused mitochondria with reduced OXPHOS. In vitro, Hes and Nar reduced MM clonogenicity and viability, even in the presence of patient-derived bone marrow stromal cells, triggering ER stress and apoptosis. Interestingly, Hes and Nar rewired MM cell metabolism through the down-regulation of master transcriptional activators (SREBF-1, c-MYC) of lipogenesis genes. An extract of Tacle, a Citrus variety rich in Hesperidin and Naringin, was capable to recapitulate the phenotypic and molecular perturbations of each flavanone, triggering anti-MM activity in vivo. Conclusion Hes and Nar inhibit proliferation, rewire the metabolism and induce apoptosis of MM cells via antagonism of the mitochondrial fission driver Drp1. These results provide a framework for the development of natural anti-MM therapeutics targeting aberrant mitochondrial dependencies.

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“…Malignant transformation associated with cancer development has been associated with abnormal mitochondrial dynamics [ 197 – 199 ]. Mitochondria exist along fragmented and fused states regulating mitochondrial metabolism and cell death, and loss of proper mitochondrial dynamics impinges on cell growth and survival [ 200 , 201 ].…”

Section: Mitochondrial Dysfunction In Cancer: Mechanisms and Therapeu...mentioning

confidence: 99%

Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer

Rocca,

Soda,

De Francesco

et al. 2023

J Transl Med

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A large body of evidence indicates the existence of a complex pathophysiological relationship between cardiovascular diseases and cancer. Mitochondria are crucial organelles whose optimal activity is determined by quality control systems, which regulate critical cellular events, ranging from intermediary metabolism and calcium signaling to mitochondrial dynamics, cell death and mitophagy. Emerging data indicate that impaired mitochondrial quality control drives myocardial dysfunction occurring in several heart diseases, including cardiac hypertrophy, myocardial infarction, ischaemia/reperfusion damage and metabolic cardiomyopathies. On the other hand, diverse human cancers also dysregulate mitochondrial quality control to promote their initiation and progression, suggesting that modulating mitochondrial homeostasis may represent a promising therapeutic strategy both in cardiology and oncology. In this review, first we briefly introduce the physiological mechanisms underlying the mitochondrial quality control system, and then summarize the current understanding about the impact of dysregulated mitochondrial functions in cardiovascular diseases and cancer. We also discuss key mitochondrial mechanisms underlying the increased risk of cardiovascular complications secondary to the main current anticancer strategies, highlighting the potential of strategies aimed at alleviating mitochondrial impairment-related cardiac dysfunction and tumorigenesis. It is hoped that this summary can provide novel insights into precision medicine approaches to reduce cardiovascular and cancer morbidities and mortalities.

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Association of mitochondrial homeostasis and dynamic balance with malignant biological behaviors of gastrointestinal cancer

Cited by 11 publications

References 132 publications

HIV-1 Reverse Transcriptase Expression in HPV16-Infected Epidermoid Carcinoma Cells Alters E6 Expression and Cellular Metabolism, and Induces a Hybrid Epithelial/Mesenchymal Cell Phenotype

HIV-1 Reverse Transcriptase Expression in HPV16-Infected Epidermoid Carcinoma Cells Alters E6 Expression and Cellular Metabolism, and Induces a Hybrid Epithelial/Mesenchymal Cell Phenotype

Targeting of mitochondrial fission through natural flavanones elicits anti-myeloma activity

Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer

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