Deactivation of Glutaminolysis Sensitizes PIK3CA-Mutated Colorectal Cancer Cells to Aspirin-Induced Growth Inhibition

Boku, Shogen; Watanabe, Motoki; Sukeno, Mamiko; Yaoi, Takeshi; Hirota, Kiichi; Iizuka-Ohashi, Mahiro; Itoh, Kyoko; Sakai, Toshiyuki

doi:10.3390/cancers12051097

Cited by 9 publications

(8 citation statements)

References 47 publications

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“…We found that GLS expression was negatively associated with the sensitivity of temsirolimus, an mTOR inhibitor. Interestingly, combining the GLS inhibitor with an mTOR inhibitor is reported to result in a combinatorial effect [ 46 , 47 , 48 ]. The upregulation of GLS was reported to be induced following mTOR inhibition, providing a theoretical basis for the combination of GLS inhibitors and mTOR inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis

Zou

et al. 2021

Genes

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Background: In recent years, metabolic reprogramming has been identified as a hallmark of cancer. Accumulating evidence suggests that glutamine metabolism plays a crucial role in oncogenesis and the tumor microenvironment. In this study, we aimed to perform a systematic and comprehensive analysis of six key metabolic node genes involved in the dynamic regulation of glutamine metabolism (referred to as GLNM regulators) across 33 types of cancer. Methods: We analyzed the gene expression, epigenetic regulation, and genomic alterations of six key GLNM regulators, including SLC1A5, SLC7A5, SLC3A2, SLC7A11, GLS, and GLS2, in pan-cancer using several open-source platforms and databases. Additionally, we investigated the impacts of these gene expression changes on clinical outcomes, drug sensitivity, and the tumor microenvironment. We also attempted to investigate the upstream microRNA–mRNA molecular networks and the downstream signaling pathways involved in order to uncover the potential molecular mechanisms behind metabolic reprogramming. Results: We found that the expression levels of GLNM regulators varied across cancer types and were related to several genomic and immunological characteristics. While the immune scores were generally lower in the tumors with higher gene expression, the types of immune cell infiltration showed significantly different correlations among cancer types, dividing them into two clusters. Furthermore, we showed that elevated GLNM regulators expression was associated with poor overall survival in the majority of cancer types. Lastly, the expression of GLNM regulators was significantly associated with PD-L1 expression and drug sensitivity. Conclusions: The elevated expression of GLNM regulators was associated with poorer cancer prognoses and a cold tumor microenvironment, providing novel insights into cancer treatment and possibly offering alternative options for the treatment of clinically refractory cancers.

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Section: Discussionmentioning

confidence: 99%

Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis

Zou

et al. 2021

Genes

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“…Previous studies reported that hepatocellular cell adhesion molecule (HepaCAM) can serve a significant role in tumour cell proliferation, apoptosis, migration and invasion, since its expression is typically absent in cancer tissues ( 19 , 45 ). In addition, previous reports have found that mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α ( PIK3CA ) can activate PI3K/AKT signalling downstream to induce alterations in Gln metabolism in tumour cells ( 29 ). In the present study, bioinformatics analyses of various databases were performed to predict the correlation in the expression levels between HepaCAM and PIK3CA.…”

Section: Discussionmentioning

confidence: 99%

“…PIK3CA can be constitutively activated by two main different mechanisms, namely activating mutation and amplification (26). Accumulating evidence has revealed that PIK3CA is associated with Gln metabolism reprogramming in numerous types of cancers (27)(28)(29)(30). Consequently, PIK3CA may also be a key regulatory target for reprogramming Gln metabolism in PCa.…”

Section: Introductionmentioning

confidence: 99%

HepaCAM‑PIK3CA axis regulates the reprogramming of glutamine metabolism to inhibit prostate cancer cell proliferation

Gao

et al. 2022

Int J Oncol

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Energy metabolism reprogramming is becoming an increasingly important hallmark of cancer. Specifically, cancers tend to undergo metabolic reprogramming to upregulate a cell-dependent glutamine (Gln) metabolism. Notably, hepatocellular cell adhesion molecule (HepaCAM) has been previously reported to serve a key role as a tumour suppressor. However, the possible regulatory role of HepaCAM in Gln metabolism in prostate cancer (PCa) remains poorly understood. In the present study, bioinformatics analysis predicted a significant negative correlation among the expression of HepaCAM, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), glutaminase (GLS) and solute carrier family 1 member 5 (SLC1A5), components of Gln metabolism, in clinical and genomic datasets. Immunohistochemistry results verified a negative correlation between HepaCAM and PIK3CA expression in PCa tissues. Subsequently, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) assays were performed, and the results revealed markedly reduced levels of Gln and metabolic flux in the blood samples of patients with PCa and in PCa cells. Mechanistically, overexpression of HepaCAM inhibited Gln metabolism and proliferation by regulating PIK3CA in PCa cells. In addition, Gln metabolism was discovered to be stress-resistant in PCa cells, since the expression levels of GLS and SLC1A5 remained high for a period of time after Gln starvation. However, overexpression of HepaCAM reversed this resistance to some extent. Additionally, alpelisib, a specific inhibitor of PIK3CA, effectively potentiated the inhibitory effects of HepaCAM overexpression on Gln metabolism and cell proliferation through mass spectrometry and CCK-8 experiments. In addition, the inhibitory effect of PIK3CA on the growth of tumor tissue in nude mice was also confirmed by immunohistochemistry in vivo. To conclude, the results from the present study revealed an abnormal Gln metabolic profile in the blood samples of patients with PCa, suggesting that it can be applied as a clinical diagnostic tool for PCa. Additionally, a key role of the HepaCAM/PIK3CA axis in regulating Gln metabolism, cell proliferation and tumour growth was identified. The combination of alpelisib treatment with the upregulation of HepaCAM expression may serve as a novel method for treating patients with PCa.

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“…Cell cycle and apoptosis induction were analyzed as previously described [ 40 ]. Briefly, after cells were seeded in 6-well plates at a density of 50,000 cells per well and incubated for 24 h, the cells were treated with the agent or siRNAs and harvested by trypsinization.…”

Section: Methodsmentioning

confidence: 99%

Rabdosianone I, a Bitter Diterpene from an Oriental Herb, Suppresses Thymidylate Synthase Expression by Directly Binding to ANT2 and PHB2

Watanabe

Yamada

Kurumida

et al. 2021

Cancers

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Natural products have numerous bioactivities and are expected to be a resource for potent drugs. However, their direct targets in cells often remain unclear. We found that rabdosianone I, which is a bitter diterpene from an oriental herb for longevity, Isodon japonicus Hara, markedly inhibited the growth of human colorectal cancer cells by downregulating the expression of thymidylate synthase (TS). Next, using rabdosianone I-immobilized nano-magnetic beads, we identified two mitochondrial inner membrane proteins, adenine nucleotide translocase 2 (ANT2) and prohibitin 2 (PHB2), as direct targets of rabdosianone I. Consistent with the action of rabdosianone I, the depletion of ANT2 or PHB2 reduced TS expression in a different manner. The knockdown of ANT2 or PHB2 promoted proteasomal degradation of TS protein, whereas that of not ANT2 but PHB2 reduced TS mRNA levels. Thus, our study reveals the ANT2- and PHB2-mediated pleiotropic regulation of TS expression and demonstrates the possibility of rabdosianone I as a lead compound of TS suppressor.

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Deactivation of Glutaminolysis Sensitizes PIK3CA-Mutated Colorectal Cancer Cells to Aspirin-Induced Growth Inhibition

Cited by 9 publications

References 47 publications

Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis

Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis

HepaCAM‑PIK3CA axis regulates the reprogramming of glutamine metabolism to inhibit prostate cancer cell proliferation

Rabdosianone I, a Bitter Diterpene from an Oriental Herb, Suppresses Thymidylate Synthase Expression by Directly Binding to ANT2 and PHB2

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