Abstract
Reprograming of proline metabolism is critical for tumor growth. Here we show that PINCH-1 is highly expressed in lung adenocarcinoma and promotes proline synthesis through regulation of mitochondrial dynamics. Knockout (KO) of PINCH-1 increases dynamin-related protein 1 (DRP1) expression and mitochondrial fragmentation, which suppresses kindlin-2 mitochondrial translocation and interaction with pyrroline-5-carboxylate reductase 1 (PYCR1), resulting in inhibition of proline synthesis and cell proliferation. Depletion of DRP1 reverses PINCH-1 deficiency-induced defects on mitochondrial dynamics, proline synthesis and cell proliferation. Furthermore, overexpression of PYCR1 in PINCH-1 KO cells restores proline synthesis and cell proliferation, and suppresses DRP1 expression and mitochondrial fragmentation. Finally, ablation of PINCH-1 from lung adenocarcinoma in mouse increases DRP1 expression and inhibits PYCR1 expression, proline synthesis, fibrosis and tumor growth. Our results identify a signaling axis consisting of PINCH-1, DRP1 and PYCR1 that regulates mitochondrial dynamics and proline synthesis, and suggest an attractive strategy for alleviation of tumor growth.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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A549 Cells
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Adenocarcinoma of Lung / genetics
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Adenocarcinoma of Lung / mortality
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Adenocarcinoma of Lung / pathology*
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Adult
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Aged
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Aged, 80 and over
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Animals
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Cell Proliferation / genetics
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Cytoskeletal Proteins / metabolism
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Disease Models, Animal
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Dynamins / metabolism
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Female
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Gene Knockout Techniques
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Humans
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LIM Domain Proteins / genetics
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LIM Domain Proteins / metabolism*
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Lung / cytology
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Lung / pathology
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Lung Neoplasms / genetics
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Lung Neoplasms / mortality
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Lung Neoplasms / pathology*
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Transgenic
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Middle Aged
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Mitochondria / metabolism
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Mitochondrial Dynamics
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Muscle Proteins / metabolism
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Neoplasm Proteins / metabolism
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Proline / biosynthesis
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Proto-Oncogene Proteins p21(ras) / genetics
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Pyrroline Carboxylate Reductases / metabolism
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Survival Analysis
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delta-1-Pyrroline-5-Carboxylate Reductase
Substances
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Adaptor Proteins, Signal Transducing
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Cytoskeletal Proteins
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FERMT3 protein, human
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LIM Domain Proteins
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LIMS1 protein, human
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Lims1 protein, mouse
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Membrane Proteins
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Muscle Proteins
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Neoplasm Proteins
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kindlin-2 protein, mouse
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Proline
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Pyrroline Carboxylate Reductases
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)
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DNM1L protein, human
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Dnm1l protein, mouse
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Dynamins