<p>Down-Regulation of SREBP via PI3K/AKT/mTOR Pathway Inhibits the Proliferation and Invasion of Non-Small-Cell Lung Cancer Cells</p>

Abstract

Background Lung cancer is one of the most common causes of cancer-related deaths worldwide, metabolic disorders are also a problem that puzzles mankind. SREBP is overexpressed in non-small-cell lung cancer (NSCLC) and is also a key regulator of lipid synthesis. However, the mechanisms by which SREBP regulates the proliferation, migration and invasion in NSCLC remain unclear. Materials and Methods CCK-8, colony formation assay, soft agar assay, scratch wound healing assay and transwell assays were performed to detect proliferation, and invasion in NSCLC cells, respectively. In addition, Western blotting assay, qPCR and immunofluorescence were applied to detect the expressions of SREBP1, SREBP2, ki-67, PCNA, Bax, bcl-2, E-cadherin, N-cadherin, Vimentin, PI3K, p-PI3k, AKT, p-AKT, mTOR, p-mTOR in NSCLC cells. Results In this study, downregulation of SREBP significantly inhibited the proliferation, migration and invasion of A549 and H1299 cells. Moreover, the method of piecewise inhibition was adopted to prove that SREBP is a downstream molecule of the PI3K/Akt/mTOR signaling pathway. Conclusion Our study indicated that downregulation of SREBP inhibited the growth in NSCLC cells via PI3K/AKT/mTOR signaling pathway. Thus, we suggested SREBP may serve as a potential target for the treatment of patients with NSCLC.

An AKT/PRMT5/SREBP1 axis in lung adenocarcinoma regulates de novo lipogenesis and tumor growth

“…45 Recently, AKT activation was reported to induce SREBP1 activation in lung adenocarcinoma cells, but the mechanisms underlying this process remain elusive. 15 Consistently, our data confirmed that AKT activation promotes mSREBP1 expression and activation in lung adenocarcinoma cells. Moreover, in addition to previously reported findings, our data indicated that, in lung adenocarcinoma, AKT hyperactivation not only upregulates SREBF1 gene expression at the transcriptional level, but also hampers the ubiquitin-proteasome pathway degradation of mSREBP1 at the post-translational level through PRMT5, inducing mSREBP1 overactivation in cancer cells, resulting in lipid synthesis and uncontrolled growth of cancer cells.…”

“…Activation of AKT also promotes post‐translational cleavage of preSREBP1 in glioblastoma 45 . Recently, AKT activation was reported to induce SREBP1 activation in lung adenocarcinoma cells, but the mechanisms underlying this process remain elusive 15 . Consistently, our data confirmed that AKT activation promotes mSREBP1 expression and activation in lung adenocarcinoma cells.…”

“…[9][10][11][12] Recently, lipid hypersynthesis in lung cancer was observed, and targeting SREBP1 was shown to hamper the tumorigenesis of lung cancer and reverse gefitinib resistance in lung cancer cells. [13][14][15] Although AKT activation has been shown to activate SREBP1 through various mechanisms to modulate lipid metabolism in several malignant tumors (eg, melanoma, glioblastoma, and breast cancer), [16][17][18][19][20][21][22] the mechanisms underlying lipid metabolism reprogramming in hyperactive AKT-driven lung cancer remain elusive.…”

“…SREBP1 is the master regulator of tumor lipid metabolism and is overexpressed in certain tumors; it is the mature form of SREBP1 (mSREBP1) that directly triggers lipid enzymes (eg, ATP citrate lyase [ACLY], fatty acid synthase [FASN], and acyl‐CoA desaturase [SCD1]) gene transcription 9‐12 . Recently, lipid hypersynthesis in lung cancer was observed, and targeting SREBP1 was shown to hamper the tumorigenesis of lung cancer and reverse gefitinib resistance in lung cancer cells 13‐15 . Although AKT activation has been shown to activate SREBP1 through various mechanisms to modulate lipid metabolism in several malignant tumors (eg, melanoma, glioblastoma, and breast cancer), 16‐22 the mechanisms underlying lipid metabolism reprogramming in hyperactive AKT‐driven lung cancer remain elusive.…”

DNA methylome analysis identifies BMI‐related epigenetic changes associated with non‐small cell lung cancer susceptibility

“…The methylations of ABCG1 and SREBF1 in whole blood were well‐known to be associated with obesity 12 . More importantly, these two genes, as potential oncogenes of lung cancer, have been found to be implicated in the proliferation and apoptosis of lung cancer cells 22,23 . However, the role of DNA methylation in the relationship between BMI and lung cancer remains largely unknown.…”