Metal Exposure Promotes Colorectal Tumorigenesis via the Aberrant N6-Methyladenosine Modification of ATP13A3

Li, Shuwei; Xu, Shenya; Chen, Yehua; Ben, Shuai; Guo, Mengfan; Chu, Haiyan; Gu, Dongying; Zhang, Zhengdong; Wang, Meilin

doi:10.1021/acs.est.2c07389

Cited by 9 publications

(3 citation statements)

References 41 publications

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“…Many cancer types rely on an increased PTS, but it is unlikely that ATP13A4 is the only P5B-ATPase that is implicated in cancer. Indeed, ATP13A2 has been implicated in several human cancers, including melanoma [ 37 ], colon cancer [ 38 ], hepatocellular carcinoma [ 39 ], acute myeloid leukemia [ 40 ] and non-small-cell lung cancer [ 41 ], while ATP13A3 has been linked to pancreatic cancer and colorectal cancer [ 42 , 43 , 44 ]. Interestingly, high expression of ATP13A3 was found in metastatic pancreatic cancer cells with high polyamine uptake compared to slowly proliferating cells with low import activity [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

ATP13A4 Upregulation Drives the Elevated Polyamine Transport System in the Breast Cancer Cell Line MCF7

et al. 2023

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Polyamine homeostasis is disturbed in several human diseases, including cancer, which is hallmarked by increased intracellular polyamine levels and an upregulated polyamine transport system (PTS). Thus far, the polyamine transporters contributing to the elevated levels of polyamines in cancer cells have not yet been described, despite the fact that polyamine transport inhibitors are considered for cancer therapy. Here, we tested whether the upregulation of candidate polyamine transporters of the P5B transport ATPase family is responsible for the increased PTS in the well-studied breast cancer cell line MCF7 compared to the non-tumorigenic epithelial breast cell line MCF10A. We found that MCF7 cells presented elevated expression of a previously uncharacterized P5B-ATPase, ATP13A4, which was responsible for the elevated polyamine uptake activity. Furthermore, MCF7 cells were more sensitive to polyamine cytotoxicity, as demonstrated by cell viability, cell death and clonogenic assays. Importantly, the overexpression of ATP13A4 WT in MCF10A cells induced a MCF7 polyamine phenotype, with significantly higher uptake of BODIPY-labeled polyamines and increased sensitivity to polyamine toxicity. In conclusion, we established ATP13A4 as a new polyamine transporter in the human PTS and showed that ATP13A4 may play a major role in the increased polyamine uptake of breast cancer cells. ATP13A4 therefore emerges as a candidate therapeutic target for anticancer drugs that block the PTS.

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Section: Discussionmentioning

confidence: 99%

ATP13A4 Upregulation Drives the Elevated Polyamine Transport System in the Breast Cancer Cell Line MCF7

et al. 2023

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“…Environmental chemicals, such as cigarette smoke and PM2.5, are known health impairments and carcinogens. [32][33][34][35] PAHs are persistent organic pollutants with high toxicity that widely exist in various environmental substrates. Barul et al examined the intensity, frequency, and certainty of exposure to PAHs among 1929 prostate cancer patients (436 with aggressive cancer) and 1994 controls in their working conditions.…”

Section: Discussionmentioning

confidence: 99%

Effect of polycyclic aromatic hydrocarbons on cancer risk causally mediated via vitamin D levels

Chen

et al. 2023

Environmental Toxicology

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Polycyclic aromatic hydrocarbons (PAHs) widely exist in environmental substrates and are closely related to individual circulating vitamin D levels and tumorigenesis. Therefore, we proposed to evaluate the relationship between PAH exposure, vitamin D, and the risks for 14 cancer types via a causal inference framework underlying the mediation analysis. We evaluated seven urine monohydroxylated PAH (OH‐PAH) and serum vitamin D concentrations of 3306 participants from the National Health and Nutrition Examination Survey between the 2013 and 2016 survey cycles and measured PAH concentrations in 150 subjects from the Nanjing cohort. We observed a significant negative dose–response relationship between increased OH‐PAH levels and vitamin D deficiency. Each unit increase in ∑OH‐PAHs could lead to a decrease in vitamin D levels (βadj = −0.98, Padj = 2.05 × 10−4). Body mass index could have interaction effects with ∑OH‐PAHs and affect vitamin D levels. Coexposure to naphthalene and fluorene metabolites mutually affected vitamin D levels. Notably, vitamin D could causally mediate the relationship between OH‐PAHs and nine types of cancer (e.g., colorectal cancer, liver cancers, etc.). This study first emphasizes the causal cascade of individual OH‐PAHs, vitamin D, and cancer risk, providing insights into prevention via the environment.

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“…Many cancer types rely on an increased PTS, but it is unlikely that ATP13A4 may be the only P5B-ATPase that is implicated in cancer. Indeed, ATP13A2 has been implicated in several human cancers, including melanoma [33], colon cancer [34], hepatocellular carcinoma [35], acute myeloid leukemia [36] and non-small cell lung cancer [37]; while ATP13A3 has been linked to pancreatic cancer and colorectal cancer [38][39][40]. Interestingly, high expression of ATP13A3 was found in metastatic pancreatic cancer cells with high polyamine uptake compared to slowly proliferating cells with low import activity [40].…”

Section: Is Atp13a4 Implicated In the Upregulated Pts Of Other Cancer...mentioning

confidence: 99%

ATP13A4 upregulation drives the elevated polyamine transport system in the breast cancer cell line MCF7

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Kourti

Ausloos

et al. 2023

Preprint

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Polyamine homeostasis is disturbed in several human diseases, including cancer, which is hallmarked by increased intracellular polyamine levels and an upregulated polyamine transport system (PTS). So far, the polyamine transporters contributing to the elevated levels of polyamines in cancer cells have not yet been described, despite the fact that polyamine transport inhibitors are considered for cancer therapy. Here, we tested whether upregulation of candidate polyamine transporters of the P5B-transport ATPase family is responsible for the increased PTS in the well-studied breast cancer cell line MCF7 compared to the non-tumorigenic epithelial breast cell line MCF10A. We found that MCF7 cells present elevated expression of a previously uncharacterized P5B-ATPase ATP13A4, which is responsible for the elevated polyamine uptake activity. Furthermore, MCF7 cells are more sensitive to polyamine cytotoxicity, as demonstrated by cell viability, cell death and clonogenic assays. Importantly, overexpression of ATP13A4 WT in MCF10A cells induces a MCF7 polyamine phenotype, with significantly higher uptake of BODIPY-labelled polyamines and increased sensitivity to polyamine toxicity. In conclusion, we establish ATP13A4 as a new polyamine transporter in the human PTS and show that ATP13A4 may play a major role in the increased polyamine uptake of breast cancer cells. ATP13A4 therefore emerges as a candidate therapeutic target for anticancer drugs that block the PTS.

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Metal Exposure Promotes Colorectal Tumorigenesis via the Aberrant N⁶-Methyladenosine Modification of ATP13A3

Cited by 9 publications

References 41 publications

ATP13A4 Upregulation Drives the Elevated Polyamine Transport System in the Breast Cancer Cell Line MCF7

ATP13A4 Upregulation Drives the Elevated Polyamine Transport System in the Breast Cancer Cell Line MCF7

Effect of polycyclic aromatic hydrocarbons on cancer risk causally mediated via vitamin D levels

ATP13A4 upregulation drives the elevated polyamine transport system in the breast cancer cell line MCF7

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