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.
Highlights
Reprograming of proline metabolism is critical for tumor growth
We recently found that a fraction of kindlin-2, a focal adhesion protein, is translocated into mitochondria where it forms a complex with pyrroline-5-carboxylate reductase 1 (PYCR1), which prevents PYCR1 degradation and thereby promotes proline synthesis, tumor fibrosis, and growth[11]
These findings identify a- PINCH-1-dynamin-related protein 1 (DRP1)-PYCR1 signaling axis that is critically involved in regulation of mitochondrial dynamics and proline synthesis, and suggest an attractive strategy for control of tumor fibrosis and growth
Summary
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. Despite the increase of PYCR1 expression, the level of proline is often inadequate for maintaining high level of protein synthesis and redox balance in proliferating cancer cells[2,10] This “proline vulnerability” may provide an opportunity for inhibition of fibrosis and tumor growth. We provide in vivo evidence showing that ablation of PINCH-1 from lung adenocarcinoma in mouse increases DRP1 expression and reduces the levels of PYCR1, proline synthesis, collagen matrix, and tumor growth. These findings identify a- PINCH-1-DRP1-PYCR1 signaling axis that is critically involved in regulation of mitochondrial dynamics and proline synthesis, and suggest an attractive strategy for control of tumor fibrosis and growth
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