Attenuation of argininosuccinate lyase inhibits cancer growth via cyclin A2 and nitric oxide

Hau Lun Huang, Hui-Ping Hsu, Shu-Chu Shiesh, Yung Sheng Chang, Wei Ching Chen, Chien Yu Cho, Chiao Fang Teng, Ih Jen Su, Wen Chun Hung, Ming-Derg Lai

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Abstract

Arginine biosynthesis and nitric oxide (NO) production are important for cancer homeostasis. Degradation of arginine may be used to inhibit liver tumors with low argininosuccinate synthetase (ASS) expression. In this report, we investigated an alternative therapeutic approach by targeting argininosuccinate lyase (ASL). ASL is transcriptionally induced by endoplasmic reticulum stress and is overexpressed in some human liver tumors. Knockdown of ASL expression by short hairpin RNA (shRNA) in three liver cancer cell lines, ML-1, HuH-7, and HepG2, decreased colony formation in vitro and tumor growth in vivo. Furthermore, lentiviral infection of ASL shRNA inhibited tumor growth in a therapeutic animal tumor model. Analysis of ASL shRNA on the cellcycle progression revealed a G2-M delay. Among cell-cycle regulatory molecules, cyclin A2 expression was reduced. Reintroduction of exogenous cyclin A2 restored the cell growth in ASL-knockdown cells. Autophagy was observed in the cells treated with ASL shRNA, as shown by an increase in LC3-II levels and autophagosome formation. The total cellular arginine level was not altered significantly. Inhibition of autophagy further attenuated cell growth, suggesting that autophagy induced by ASL shRNA plays a feedback prosurvival function. Knockdown of ASL reduced NO content, and addition of NO donor partially recovered the growth inhibition by ASL shRNA. In summary, downregulation of ASL attenuated tumor growth and the inhibition was mainly mediated by a decrease of cyclin A2 and NO. Mol Cancer Ther; 12(11); 2505-16.

Original languageEnglish
Pages (from-to)2505-2516
Number of pages12
JournalMolecular Cancer Therapeutics
Volume12
Issue number11
DOIs
Publication statusPublished - 2013 Jan 1

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Cyclin A2
Argininosuccinate Lyase
Nitric Oxide
Growth
Small Interfering RNA
Neoplasms
Autophagy
Arginine
Argininosuccinate Synthase
Endoplasmic Reticulum Stress
Nitric Oxide Donors
Liver
Liver Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Huang, Hau Lun ; Hsu, Hui-Ping ; Shiesh, Shu-Chu ; Chang, Yung Sheng ; Chen, Wei Ching ; Cho, Chien Yu ; Teng, Chiao Fang ; Su, Ih Jen ; Hung, Wen Chun ; Lai, Ming-Derg. / Attenuation of argininosuccinate lyase inhibits cancer growth via cyclin A2 and nitric oxide. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 11. pp. 2505-2516.
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abstract = "Arginine biosynthesis and nitric oxide (NO) production are important for cancer homeostasis. Degradation of arginine may be used to inhibit liver tumors with low argininosuccinate synthetase (ASS) expression. In this report, we investigated an alternative therapeutic approach by targeting argininosuccinate lyase (ASL). ASL is transcriptionally induced by endoplasmic reticulum stress and is overexpressed in some human liver tumors. Knockdown of ASL expression by short hairpin RNA (shRNA) in three liver cancer cell lines, ML-1, HuH-7, and HepG2, decreased colony formation in vitro and tumor growth in vivo. Furthermore, lentiviral infection of ASL shRNA inhibited tumor growth in a therapeutic animal tumor model. Analysis of ASL shRNA on the cellcycle progression revealed a G2-M delay. Among cell-cycle regulatory molecules, cyclin A2 expression was reduced. Reintroduction of exogenous cyclin A2 restored the cell growth in ASL-knockdown cells. Autophagy was observed in the cells treated with ASL shRNA, as shown by an increase in LC3-II levels and autophagosome formation. The total cellular arginine level was not altered significantly. Inhibition of autophagy further attenuated cell growth, suggesting that autophagy induced by ASL shRNA plays a feedback prosurvival function. Knockdown of ASL reduced NO content, and addition of NO donor partially recovered the growth inhibition by ASL shRNA. In summary, downregulation of ASL attenuated tumor growth and the inhibition was mainly mediated by a decrease of cyclin A2 and NO. Mol Cancer Ther; 12(11); 2505-16.",
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Attenuation of argininosuccinate lyase inhibits cancer growth via cyclin A2 and nitric oxide. / Huang, Hau Lun; Hsu, Hui-Ping; Shiesh, Shu-Chu; Chang, Yung Sheng; Chen, Wei Ching; Cho, Chien Yu; Teng, Chiao Fang; Su, Ih Jen; Hung, Wen Chun; Lai, Ming-Derg.

In: Molecular Cancer Therapeutics, Vol. 12, No. 11, 01.01.2013, p. 2505-2516.

Research output: Contribution to journalArticle

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AU - Hsu, Hui-Ping

AU - Shiesh, Shu-Chu

AU - Chang, Yung Sheng

AU - Chen, Wei Ching

AU - Cho, Chien Yu

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AU - Su, Ih Jen

AU - Hung, Wen Chun

AU - Lai, Ming-Derg

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