PINCH-1 promotes Δ1-pyrroline-5-carboxylate synthase expression and contributes to proline metabolic reprogramming in lung adenocarcinoma

Cui，Chunhong1; Wang，Jiaxin1; Guo，Ling1; Wu，Chuanyue2

2021

10.1007/s00726-021-03050-3

AMINO ACIDS   影响因子和分区

0939-4451

1438-2199

Proline metabolic reprogramming is intimately involved in cancer progression. We recently identified a critical role of PINCH-1, a cell-extracellular matrix (ECM) adhesion protein whose expression is elevated in lung adenocarcinoma, in the promotion of proline biosynthesis, fibrosis and lung adenocarcinoma growth. How PINCH-1 promotes proline biosynthesis, however, was incompletely understood. In this study, we show that PINCH-1 promotes the expression of Δ-pyrroline-5-carboxylate synthase (P5CS), a key enzyme that links glutamate metabolism to proline biosynthesis. Depletion of PINCH-1 from lung adenocarcinoma cells reduced the protein but not mRNA level of P5CS, resulting in down-regulation of the cellular level of P5C and cell proliferation. Treatment of the cells with protease inhibitor leupeptin effectively reversed PINCH-1 deficiency-induced reduction of the P5CS level. At the molecular level, PINCH-1, through its LIM2 domain, physically associated with P5CS in lung adenocarcinoma cells. Re-expression of wild type PINCH-1, but not that of the PINCH-1 LIM2 deletion mutant, in PINCH-1 deficient lung adenocarcinoma cells restored P5CS expression, proline biosynthesis and cell proliferation. Finally, P5CS expression, like that of PINCH-1, is elevated in human and mouse lung adenocarcinoma. Using a mouse model of lung adenocarcinoma in which PINCH-1 is conditionally ablated, we show that knockout of PINCH-1 from lung adenocarcinoma effectively reduced the P5CS level in vivo. Our results reveal an important role of PINCH-1 in the promotion of P5CS expression, which likely contributes to proline metabolic reprogramming and consequently lung adenocarcinoma progression.

Fibrosis Lung adenocarcinoma PINCH-1 Proline synthesis Pyrroline-5-carboxylate synthase

SCI

英语

第一 ; 通讯

WOS:000675143900003

BIOLOGY & BIOCHEMISTRY

2-s2.0-85110880203

Scopus

1.Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment,Academy for Advanced Interdisciplinary Studies and Department of Biology,Southern University of Science and Technology,Shenzhen,China
2.Department of Pathology,University of Pittsburgh School of Medicine,Pittsburgh,15261,United States

Cui，Chunhong,Wang，Jiaxin,Guo，Ling,et al. PINCH-1 promotes Δ1-pyrroline-5-carboxylate synthase expression and contributes to proline metabolic reprogramming in lung adenocarcinoma[J]. AMINO ACIDS,2021.

Cui，Chunhong,Wang，Jiaxin,Guo，Ling,&Wu，Chuanyue.(2021).PINCH-1 promotes Δ1-pyrroline-5-carboxylate synthase expression and contributes to proline metabolic reprogramming in lung adenocarcinoma.AMINO ACIDS.

Cui，Chunhong,et al."PINCH-1 promotes Δ1-pyrroline-5-carboxylate synthase expression and contributes to proline metabolic reprogramming in lung adenocarcinoma".AMINO ACIDS (2021).