Argininosuccinate Synthase 1-Deficiency Enhances the Cell Sensitivity to Arginine through Decreased DEPTOR Expression in Endometrial Cancer

Ohshima, Kenji; Nojima, Satoshi; Tahara, Shinichiro; Kurashige, Masako; Hori, Yumiko; Hagiwara, Kohei; Okuzaki, Daisuke; Oki, Sadaaki; Wada, Naoki; Ikeda, Jun; Kanai, Yoshikatsu; Morii, Eiichi

doi:10.1038/srep45504

Cited by 25 publications

(17 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Two dye-swapped experiments were performed on a Whole Human Genome Oligo Microarray ver. 2 (G4845A; Agilent Technologies, Boeblingen, Germany) as described previously [26]. The Subio Platform and Subio Basic Plug-in (v1.19; Subio Inc., Aichi, Japan) were used to calculate the fold change between samples with the twotailed Student's t-test.…”

Section: Microarray Analysismentioning

confidence: 99%

Adenylosuccinate lyase enhances aggressiveness of endometrial cancer by increasing killer cell lectin-like receptor C3 expression by fumarate

Park

Ohshima

Nojima

et al. 2018

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

Adenylosuccinate lyase (ADSL) is an enzyme that plays important roles in de novo purine synthesis. Although ADSL was reported to be upregulated in various malignancies, such as colorectal, breast, and prostate cancer, as well as gliomas, the mechanism by which elevated ADSL expression contributes to cancer has not been elucidated. We previously performed a shotgun proteomics analysis to characterize specific proteins associated with the properties of the aldehyde dehydrogenase (ALDH)-high cell population, which was reported to be involved in tumorigenic potential, and showed that ADSL expression is upregulated in the ALDH-high population of endometrial cancer. Here, we showed that ADSL is involved in endometrial cancer aggressiveness by regulating expression of killer cell lectin-like receptor C3 (KLRC3), which is a receptor expressed on natural killer cells. Immunohistochemical analysis indicated that ADSL expression increased as endometrioid carcinoma specimens became more poorly differentiated and higher degree of primary tumor progression. Knockdown of ADSL in endometrial cancer cells decreased cell proliferation, migration, and invasive capability, and caused the cells to adopt a more rounded shape. DNA microarray analysis and quantitative real-time PCR showed that KLRC3 expression was decreased in ADSL knockdown cells. Knockdown of KLRC3 in endometrial cancer cells resulted in the same phenotype as knockdown of ADSL. Moreover, fumarate, which could be produced by ADSL and was recently shown to be an oncometabolite, recovered KLRC3 expression in ADSL knockdown cells, suggesting that fumarate produced by ADSL could regulate KLRC3 expression. Our findings indicate that ADSL enhances cell proliferation, migration, and invasive capability through regulation of KLRC3 expression by fumarate.

show abstract

Section: Microarray Analysismentioning

confidence: 99%

Adenylosuccinate lyase enhances aggressiveness of endometrial cancer by increasing killer cell lectin-like receptor C3 expression by fumarate

Park

Ohshima

Nojima

et al. 2018

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

show abstract

“…The rapid growth of tumors requires a tremendous supply of nutrients including arginine. Tumor cells exhibiting ASS gene deficiency such as endometrial cancer are more sensitive to arginine deprivation than normal cells [15]. Based on the cancer tissue specificity of ASS expression [4], we used MRC5 (ASS+), PC3 (ASS-), and HepG2 (ASS-) cell lines to explore whether ADI had the same effect on different cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway by inhibiting cytosolic ferritin and inducing chromatin autophagy

et al. 2020

View full text Add to dashboard Cite

Background: Based on its low toxicity, arginine starvation therapy has the potential to cure malignant tumors that cannot be treated surgically. The Arginine deiminase (ADI) gene has been identified to be an ideal cancersuppressor gene. ADI expressed in the cytosol displays higher oncolytic efficiency than ADI-PEG20 (Pegylated Arginine Deiminase by PEG 20,000). However, it is still unknown whether cytosolic ADI has the same mechanism of action as ADI-PEG20 or other underlying cellular mechanisms. Methods: The interactions of ADI with other protein factors were screened by yeast hybrids, and verified by coimmunoprecipitation and immunofluorescent staining. The effect of ADI inhibiting the ferritin light-chain domain (FTL) in mitochondrial damage was evaluated by site-directed mutation and flow cytometry. Control of the mitochondrial apoptosis pathway was analyzed by Western Blotting and real-time PCR experiments. The effect of p53 expression on cancer cells death was assessed by siTP53 transfection. Chromatin autophagy was explored by immunofluorescent staining and Western Blotting. Results: ADI expressed in the cytosol inhibited the activity of cytosolic ferritin by interacting with FTL. The inactive mutant of ADI still induced apoptosis in certain cell lines of ASS-through mitochondrial damage. Arginine starvation also generated an increase in the expression of p53 and p53AIP1, which aggravated the cellular mitochondrial damage. Chromatin autophagy appeared at a later stage of arginine starvation. DNA damage occurred along with the entire arginine starvation process. Histone 3 (H3) was found in autophagosomes, which implies that cancer cells attempted to utilize the arginine present in histones to survive during arginine starvation. Conclusions: Mitochondrial damage is the major mechanism of cell death induced by cytosolic ADI. The process of chromatophagy does not only stimulate cancer cells to utilize histone arginine but also speeds up cancer cell death at a later stage of arginine starvation.

show abstract

“…Tumor cells with ASS gene deficiency are more sensitive to arginine deprivation than normal cells, for example endometrial cancer [15]. ADI-PEG20 had been proved to induce cellular autophagy and caspase-independent apoptosis through exhausting the arginine in blood [16].…”

Section: Discussionmentioning

confidence: 99%

Intracellular expression of arginine deimimase activates the mitochondrial apoptosis pathway through inhibiting cytosolic ferritin and inducing chromotin autophagy

Feng

Bian

Luo

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Based on its low toxicity, arginine starvation therapy has the potential to treat those malignant tumors that can’t be treated by surgery. Arginine deiminase (ADI; EC 3.5.3.6) gene is indicated to be an ideal cancer-suppressor gene. ADI expressed in cytosol displayed higher oncolytic efficiency than ADI-PEG20 (Pegylated Arginine Deiminase by PEG 20,000)[1]. However, it is still unknown whether cytosolic ADI has the same function mechanism as ADI-PEG20 or other underlying mechanisms in cells. Methods The interaction of ADI and other protein factors was screened by yeast hybrid, and verified by co-immunoprecipitation and immunofluorescent staining. The effect of ADI inhibiting ferritin light-chain domain (FTL) on mitochondria damage was evaluated by site-directed mutation and flow cytometry. The apoptosis pathway of mitochondria control was analyzed by Western Blot and real-time PCR. The effect of p53 expression on cancer cell death was assessed by siTP53 transfection. The chromatin autophagy was explored by immunofluorescent staining and Western Blot. Results ADI expressed in cytosol inhibited the activity of cytosolic ferritin through interacting with FTL. The inactive mutant of ADI still aroused the apoptosis of some cells through mitochondria damage. Arginine deprivation also induced the expression increase of p53 and p53AIP1, which aggravated cellular mitochondria damage. Chromatin autophagy appeared at the later stage of arginine deprivation. DNA damage came along with the whole process of arginine starvation. Histone 3 (H3) was found in autophagosomes, which implied that cancer cells try to utilize the arginine in histones to survive during arginine starvation. Conclusions Mitochondria damage is the major mechanism for ADI expressed in cytosol to induce cancer cell death. Chromatophagy accumulation not only drives cancer cell to utilize histone arginine but also speeds up cancer cell death at the later time point of arginine deprivation.

show abstract

Argininosuccinate Synthase 1-Deficiency Enhances the Cell Sensitivity to Arginine through Decreased DEPTOR Expression in Endometrial Cancer

Cited by 25 publications

References 33 publications

Adenylosuccinate lyase enhances aggressiveness of endometrial cancer by increasing killer cell lectin-like receptor C3 expression by fumarate

Adenylosuccinate lyase enhances aggressiveness of endometrial cancer by increasing killer cell lectin-like receptor C3 expression by fumarate

Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway by inhibiting cytosolic ferritin and inducing chromatin autophagy

Intracellular expression of arginine deimimase activates the mitochondrial apoptosis pathway through inhibiting cytosolic ferritin and inducing chromotin autophagy

Contact Info

Product

Resources

About