Sensitization of hepatocellular carcinoma cells towards doxorubicin and sorafenib is facilitated by glucose-dependent alterations in reactive oxygen species, P-glycoprotein and DKK4

Chouhan, Surbhi; Singh, Shweta; Athavale, Dipti; Ramteke, Pranay; Vanuopadath, Muralidharan; Nair, Bipin G.; Nair, Sudarslal Sadasivan; Bhat, Manoj Kumar

doi:10.1007/s12038-020-00065-y

Cited by 26 publications

(9 citation statements)

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“…Thereafter, cells were treated with inhibitors as per experimental conditions. Cell were then processed and permeabilized as described earlier [ 72 ]. Next, the cells were incubated with the primary antibodies, FLAG mouse monoclonal or LC3B-II mouse monoclonal and TOMM20 rabbit polyclonal at a dilution of 1:500 in blocking buffer for 1 h. The excess antibody was washed off with 1X PBS.…”

Section: Methodsmentioning

confidence: 99%

“…VCaP cells or WT-ATP5F1A or Mut-ATP5F1A retroviral infected cells (3x10 5 ) were plated in 35 mm culture dish and allowed to adhere for 24 h. Next, cells were pretreated with 3-MA or Mdivi-1 for 12 h followed by 72 h of ( R )-9b treatment. Thereafter, cells were processed for fluorescence-activated cell sorting (FACS) analysis for detection of apoptotic cells, by double staining with ANXA5/annexin V-FITC along with PI as described earlier [ 72 , 74 ]. Cells were sorted by flow cytometer (BD FACS Calibur) to determine the live and dead cell populations.…”

Section: Methodsmentioning

confidence: 99%

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TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability

et al. 2022

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The challenge of rapid macromolecular synthesis enforces the energy-hungry cancer cell mitochondria to switch their metabolic phenotypes, accomplished by activation of oncogenic tyrosine kinases. Precisely how kinase activity is directly exploited by cancer cell mitochondria to meet high-energy demand, remains to be deciphered. Here we show that a non-receptor tyrosine kinase, TNK2/ACK1 (tyrosine kinase non receptor 2), phosphorylated ATP5F1A (ATP synthase F1 subunit alpha) at Tyr243 and Tyr246 (Tyr200 and 203 in the mature protein, respectively) that not only increased the stability of complex V, but also increased mitochondrial energy output in cancer cells. Further, phospho-ATP5F1A (p-Y-ATP5F1A) prevented its binding to its physiological inhibitor, ATP5IF1 (ATP synthase inhibitory factor subunit 1), causing sustained mitochondrial activity to promote cancer cell growth. TNK2 inhibitor, ( R )- 9b reversed this process and induced mitophagy-based autophagy to mitigate prostate tumor growth while sparing normal prostate cells. Further, depletion of p-Y-ATP5F1A was needed for ( R )- 9b -mediated mitophagic response and tumor growth. Moreover, Tnk2 transgenic mice displayed increased p-Y-ATP5F1A and loss of mitophagy and exhibited formation of prostatic intraepithelial neoplasia (PINs). Consistent with these data, a marked increase in p-Y-ATP5F1A was seen as prostate cancer progressed to the malignant stage. Overall, this study uncovered the molecular intricacy of tyrosine kinase-mediated mitochondrial energy regulation as a distinct cancer cell mitochondrial vulnerability and provided evidence that TNK2 inhibitors can act as “mitocans” to induce cancer-specific mitophagy. Abbreviations : ATP5F1A: ATP synthase F1 subunit alpha; ATP5IF1: ATP synthase inhibitory factor subunit 1; CRPC: castration-resistant prostate cancer; DNM1L: dynamin 1 like; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Mdivi-1: mitochondrial division inhibitor 1; Mut-ATP5F1A: Y243,246A mutant of ATP5F1A; OXPHOS: oxidative phosphorylation; PC: prostate cancer; PINK1: PTEN induced kinase 1; p-Y-ATP5F1A: phosphorylated tyrosine 243 and 246 on ATP5F1A; TNK2/ACK1: tyrosine kinase non receptor 2; Ub: ubiquitin; WT: wild type

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability

et al. 2022

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“…Altered glucose uptake and metabolism represent pivotal characteristics of cancer cells, including HCC. Increased glucose utilization in HCC cells was associated with increased intracellular ROS levels and reduced P-gp protein level, which contributes to enhance the cytotoxicity of the cancer cells to induces cell death (Chouhan et al, 2020). A nonreceptor tyrosine kinase, TNK2/ACK1 phosphorylated ATP5F1A at Tyr243 and Tyr246 that increased the stability of complex V, and increased mitochondrial energy output in cancer cells (Chouhan et al, 2023).…”

Section: Fap Overexpression In Cafs Promoted Proliferation and Migrat...mentioning

confidence: 99%

Fibroblast activation protein promotes progression of hepatocellular carcinoma via regulating the immunity

Wang,

Niu,

Yang

et al. 2024

Cell Biology International

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Fibroblast activation protein (FAP) has been indicated to express in cancer‐associated fibroblasts (CAFs) in most cancers. This work was dedicated to exploring FAP's effects on hepatocellular carcinoma (HCC). The data were extracted from The Cancer Genome Atlas, Gene Expression Omnibus, ImmPort, and Reactome databases. The correlation between FAP and HCC patients' prognosis was explored via survival analysis. The qRT‐PCR and western blot analysis were used to analyze the FAP mRNA and protein expression levels, respectively. The cell proliferation and apoptosis were determined using the cell counting kit‐8 assay kit and Annexin V‐FITC/PI apoptosis kit, respectively. The HCC patients with FAP overexpression displayed a worse prognosis. The FAP expression was positively associated with the infiltration levels of tumor purity, B cell, CD8 + T cell, CD4 + T cell, macrophage, neutrophil, and dendritic cell. The optimal nine immune related genes were screened between two groups (FAP high vs. low). Moreover, we identified 24 energy metabolism related genes (FAP high vs. low) and these 24 genes were highly expressed in the high FAP expression group. The FAP expression had a significant positive correlation with the expression of PD‐1, CTLA4, PDL‐1, and PDL‐2. The FAP overexpression promoted proliferation and migration while inhibiting the apoptosis of HCC cells. The FAP overexpression promoted the progression of HCC by regulating the immunity to affect the prognosis of HCC patients, thereby serving as a poor prognostic marker for HCC patients.

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“…It has recently been found that DKK2 can also activate the WNT signaling pathway [ 8 , 9 ]. In contrast, DKK4 has mainly been associated with a large number of H. sapiens cancers, including colorectal cancer [ 10 ], melanomas [ 11 ], hepatocellular carcinomas [ 12 ], and gastric cancer [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Whole-Genome Identification and Characterization of the DKK Gene Family and Its Transcription Profiles: An Analysis of the Chinese Soft-Shell Turtle (Pelodiscus sinensis)

Wang,

Zhu,

Chen

et al. 2024

Animals

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The DKK family is a canonical small family of WNT antagonists. Though recent studies have suggested that the DKK gene family may be involved in sex differentiation in Pelodiscus sinensis, there are still a lot of things about the DKK gene family that we do not know. In this study, we used bioinformatics methods to identify members of the DKK gene family in P. sinensis and analyzed their phylogeny, covariance, gene structure, structural domains, promoter conserved sites, signal peptides, gonadal transcription factors, transcriptional profiles, and tissue expression profiles. Additionally, qRT-PCR results were utilized for the validation and preliminary investigation of the function of the DKK gene family in P. sinensis. The results showed that the DKK gene family is divided into six subfamilies, distributed on six different chromosomal scaffolds containing different gene structures and conserved motifs with the same structural domains, and all of the members were secreted proteins. Our transcriptional profiling and embryonic expression analysis showed that DKKL1 and DKK4 were significantly expressed in the testes, whereas DKK1 and DKK3 were significantly upregulated in the ovaries. This suggests a potential function in sex differentiation in P. sinensis. Our results may provide a basic theoretical basis for the sex differentiation process in P. sinensis.

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Sensitization of hepatocellular carcinoma cells towards doxorubicin and sorafenib is facilitated by glucose-dependent alterations in reactive oxygen species, P-glycoprotein and DKK4

Cited by 26 publications

References 63 publications

TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability

TNK2/ACK1-mediated phosphorylation of ATP5F1A (ATP synthase F1 subunit alpha) selectively augments survival of prostate cancer while engendering mitochondrial vulnerability

Fibroblast activation protein promotes progression of hepatocellular carcinoma via regulating the immunity

Whole-Genome Identification and Characterization of the DKK Gene Family and Its Transcription Profiles: An Analysis of the Chinese Soft-Shell Turtle (Pelodiscus sinensis)

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