Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased cytoplasmic lipid droplets (LDs) and elevated AKT/mTOR signaling are characteristics of clear cell renal cell carcinoma (ccRCC). Lysophosphatidic acid (LPA), a potent lipid mitogen generated via autotaxin (elevated in ccRCC), can modulate tumor progression but its role in altering chemotherapeutic sensitivity to mTOR inhibitors is unclear and thus is the focus of the studies presented herein. Using malignant (A-498, 769-P and 786-O) and normal immortalized kidney (HK-2) cell lines, we investigated their cellular responsiveness to Temsirolimus (TEMS, mTOR inhibitor) in the absence or presence of LPA by monitoring alterations in AKT/mTOR pathway mediators (via western blotting), LDs (using LipidTOX and real-time PCR to assess transcript changes in modulators of LD biogenesis/turnover), mitochondrial networks (via immunofluorescence staining for TOM20 and TOM70), as well as cellular viability. We identified that TEMS reduced cellular viability in all renal cell lines, with increased sensitivity in the presence of an autophagy inhibitor. TEMS also altered activation of AKT/mTOR pathway mediators, abundance of LDs, and fragmentation of mitochondrial networks. We observed that these effects were antagonized by LPA. In HK-2 cells, LPA markedly increased LD size and abundance, coinciding with phospho-MAPK and phospho-S6 activation, increased diacylglycerol O-acetyltransferase 2 (DGAT2) mRNA (which produces triacylglycerides), and survival. Inhibiting MAPK partially antagonized LPA-induced LD changes. Collectively, we have identified that LPA can reverse the effects of TEMS by increasing LDs in a MAPK-dependent manner; these results suggest that LPA may contribute to the pathogenesis and chemotherapeutic resistance of ccRCC.
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PMID:Lysophosphatidic acid reverses Temsirolimus-induced changes in lipid droplets and mitochondrial networks in renal cancer cells. 3249 43

Peritoneal dissemination and malignant ascites in pancreatic ductal adenocarcinoma (PDAC) patients represent a major clinical issue. Lysophosphatidic acid (LPA) is a lipid mediator that modulates various cancer progression. Based on the increasing evidence showing that LPA is abundant in malignant ascites, we focused on Autotaxin (ATX), which is a secreted enzyme that is important for the production of LPA. This study aimed to elucidate the importance of the ATX-LPA axis in malignant ascites in PDAC, and to determine whether ATX works as a molecular target for treating peritoneal dissemination. In a PDAC peritoneal dissemination mouse model, the amount of ATX was significantly higher in ascites than in serum. An in vitro study using two PDAC cell lines, AsPC-1 and PANC-1, showed that ATX-LPA signaling promoted cancer cell migration via the activation of the downstream signaling, and this increased cell migration was suppressed by an ATX inhibitor, PF-8380. An in vivo study showed that PF-8380 suppressed peritoneal dissemination and decreased malignant ascites, and these results were validated by the biological analysis as well as the in vitro study. Moreover, there was a positive correlation between the amount of ATX in ascites and the degree of disseminated cancer progression. These findings demonstrated that ATX in ascites works as a promotor of peritoneal dissemination, and the targeting of ATX must represent a useful and novel therapy for peritoneal dissemination of PDAC.
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PMID:Autotaxin in ascites promotes peritoneal dissemination in pancreatic cancer. 3305 68


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