CA9 Silencing Promotes Mitochondrial Biogenesis, Increases Putrescine Toxicity and Decreases Cell Motility to Suppress ccRCC Progression

MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China

Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing 100043, China

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2020, 21(16), 5939; https://doi.org/10.3390/ijms21165939

Received: 17 June 2020 / Revised: 11 August 2020 / Accepted: 17 August 2020 / Published: 18 August 2020

(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)

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Abstract

Carbonic anhydrase IX (CA9), a pH-regulating transmembrane protein, is highly expressed in solid tumors, and particularly in clear cell renal cell carcinoma (ccRCC). The catalytic mechanisms of CA9 are well defined, but its roles in mediating cell migration/invasion and survival in ccRCC remain to be determined. Here, we confirmed that the mRNA expression of CA9 in ccRCC was significantly higher than that in para-carcinoma tissues from analysis of the datasets in The Cancer Genome Atlas. CA9 knockdown upregulated oxidative phosphorylation-associated proteins and increased mitochondrial biogenesis, resulting in the reversal of the Warburg phenotype and the inhibition of cell growth. Our study revealed that CA9 knockdown upregulated mitochondrial arginase 2 (ARG2), leading to the accumulation of putrescine, which suppressed ccRCC proliferation. Surfaceomics analysis revealed that CA9 knockdown downregulated proteins associated with extracellular matrix (ECM)—receptor interaction and cell adhesion, resulting in decreased cell migration. CA9 silencing also downregulated amino acid transporters, leading to reduced cellular amino acids. Collectively, our data show that CA9 knockdown suppresses proliferation via metabolic reprogramming and reduced cell migration, reaffirming that CA9 is a potential therapeutic target for ccRCC treatment. View Full-Text

Keywords: CA9; ccRCC; proteomics; metabolomics; surfaceomics; mitochondrial biogenesis; putrescine toxicity; motility

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MDPI and ACS Style

Xu, J.; Zhu, S.; Xu, L.; Liu, X.; Ding, W.; Wang, Q.; Chen, Y.; Deng, H. CA9 Silencing Promotes Mitochondrial Biogenesis, Increases Putrescine Toxicity and Decreases Cell Motility to Suppress ccRCC Progression. Int. J. Mol. Sci. 2020, 21, 5939. https://doi.org/10.3390/ijms21165939

AMA Style

Xu J, Zhu S, Xu L, Liu X, Ding W, Wang Q, Chen Y, Deng H. CA9 Silencing Promotes Mitochondrial Biogenesis, Increases Putrescine Toxicity and Decreases Cell Motility to Suppress ccRCC Progression. International Journal of Molecular Sciences. 2020; 21(16):5939. https://doi.org/10.3390/ijms21165939

Chicago/Turabian Style

Xu, Jiatong, Songbiao Zhu, Lina Xu, Xiaohui Liu, Wenxi Ding, Qingtao Wang, Yuling Chen, and Haiteng Deng. 2020. "CA9 Silencing Promotes Mitochondrial Biogenesis, Increases Putrescine Toxicity and Decreases Cell Motility to Suppress ccRCC Progression" International Journal of Molecular Sciences 21, no. 16: 5939. https://doi.org/10.3390/ijms21165939

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CA9 Silencing Promotes Mitochondrial Biogenesis, Increases Putrescine Toxicity and Decreases Cell Motility to Suppress ccRCC Progression

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