Abstract:Background: Statins, which are used to lower blood cholesterol levels by inhibiting HMG-CoA reductase, have shown anticancer effects in many cancer cells. However, the role of statins in gastric cancer remains unclear. This study aims to investigate whether the statins could antagonize progression of gastric cancer cells and tried to find the molecule mechanism. Methods: Effects of simvastatin on the morphology, proliferation, migration, apoptosis, and invasion of gastric cancer cells were detected and compare… Show more
“…Several recent studies have explored the functional importance of RhoA and other Ras GTPases [ 15 , 23 , 29 , 35 , 36 ], with RhoA hyperactivation having been linked to proliferation and chemoresistance in gastric, bladder, and non-small cell lung cancer [ 15 , 20 , 37 , 38 ]. The importance of RhoA-mediated YAP modulation following MPPa-PDT treatment in OS, however, has not been previously studied.…”
Background
Osteosarcoma (OS) is the most prevalent primary bone malignancy affecting adolescents, yet the emergence of chemoradiotherapeutic resistance has limited efforts to cure affected patients to date. Pyropheophorbide-α methyl ester-mediated photodynamic therapy (MPPa-PDT) is a recently developed, minimally invasive treatment for OS that is similarly constrained by such therapeutic resistance. This study sought to explore the mechanistic basis for RhoA-activated YAP1 (YAP)-mediated resistance in OS.
Methods
The relationship between YAP expression levels and patient prognosis was analyzed, and YAP levels in OS cell lines were quantified. Immunofluorescent staining was used to assess YAP nuclear translocation. OS cell lines (HOS and MG63) in which RhoA and YAP were knocked down or overexpressed were generated using lentiviral vectors. CCK-8 assays were used to examine OS cell viability, while the apoptotic death of these cells was monitored via Hoechst staining, Western blotting, and flow cytometry. Tumor-bearing nude mice were additionally used to assess the relationship between lentivirus-mediated alterations in RhoA expression and MPPa-PDT treatment outcomes. TUNEL and immunohistochemical staining approaches were leveraged to assess apoptotic cell death in tissue samples.
Results
OS patients exhibited higher levels of YAP expression, and these were correlated with a poor prognosis. MPPa-PDT induced apoptosis in OS cells, and such MPPa-PDT-induced apoptosis was enhanced following YAP knockdown whereas it was suppressed by YAP overexpression. RhoA and YAP expression levels were positively correlated in OS patients, and both active and total RhoA protein levels rose in OS cells following MPPa-PDT treatment. When RhoA was knocked down, levels of unphosphorylated YAP and downstream target genes were significantly reduced, while RhoA/ROCK2/LIMK2 pathway phosphorylation was suppressed, whereas RhoA overexpression resulted in the opposite phenotype. MPPa-PDT treatment was linked to an increase in HMGCR protein levels, and the inhibition of RhoA or HMGCR was sufficient to suppress RhoA activity and to decrease the protein levels of YAP and its downstream targets. Mevalonate administration partially reversed these reductions in the expression of YAP and YAP target genes. RhoA knockdown significantly enhanced the apoptotic death of OS cells in vitro and in vivo following MPPa-PDT treatment, whereas RhoA overexpression had the opposite effect.
Conclusions
These results suggest that the mevalonate pathway activates RhoA, which in turn activates YAP and promotes OS cell resistance to MPPa-PDT therapy. Targeting the RhoA/ROCK2/LIMK2/YAP pathway can significantly improve the efficacy of MPPa-PDT treatment for OS.
“…Several recent studies have explored the functional importance of RhoA and other Ras GTPases [ 15 , 23 , 29 , 35 , 36 ], with RhoA hyperactivation having been linked to proliferation and chemoresistance in gastric, bladder, and non-small cell lung cancer [ 15 , 20 , 37 , 38 ]. The importance of RhoA-mediated YAP modulation following MPPa-PDT treatment in OS, however, has not been previously studied.…”
Background
Osteosarcoma (OS) is the most prevalent primary bone malignancy affecting adolescents, yet the emergence of chemoradiotherapeutic resistance has limited efforts to cure affected patients to date. Pyropheophorbide-α methyl ester-mediated photodynamic therapy (MPPa-PDT) is a recently developed, minimally invasive treatment for OS that is similarly constrained by such therapeutic resistance. This study sought to explore the mechanistic basis for RhoA-activated YAP1 (YAP)-mediated resistance in OS.
Methods
The relationship between YAP expression levels and patient prognosis was analyzed, and YAP levels in OS cell lines were quantified. Immunofluorescent staining was used to assess YAP nuclear translocation. OS cell lines (HOS and MG63) in which RhoA and YAP were knocked down or overexpressed were generated using lentiviral vectors. CCK-8 assays were used to examine OS cell viability, while the apoptotic death of these cells was monitored via Hoechst staining, Western blotting, and flow cytometry. Tumor-bearing nude mice were additionally used to assess the relationship between lentivirus-mediated alterations in RhoA expression and MPPa-PDT treatment outcomes. TUNEL and immunohistochemical staining approaches were leveraged to assess apoptotic cell death in tissue samples.
Results
OS patients exhibited higher levels of YAP expression, and these were correlated with a poor prognosis. MPPa-PDT induced apoptosis in OS cells, and such MPPa-PDT-induced apoptosis was enhanced following YAP knockdown whereas it was suppressed by YAP overexpression. RhoA and YAP expression levels were positively correlated in OS patients, and both active and total RhoA protein levels rose in OS cells following MPPa-PDT treatment. When RhoA was knocked down, levels of unphosphorylated YAP and downstream target genes were significantly reduced, while RhoA/ROCK2/LIMK2 pathway phosphorylation was suppressed, whereas RhoA overexpression resulted in the opposite phenotype. MPPa-PDT treatment was linked to an increase in HMGCR protein levels, and the inhibition of RhoA or HMGCR was sufficient to suppress RhoA activity and to decrease the protein levels of YAP and its downstream targets. Mevalonate administration partially reversed these reductions in the expression of YAP and YAP target genes. RhoA knockdown significantly enhanced the apoptotic death of OS cells in vitro and in vivo following MPPa-PDT treatment, whereas RhoA overexpression had the opposite effect.
Conclusions
These results suggest that the mevalonate pathway activates RhoA, which in turn activates YAP and promotes OS cell resistance to MPPa-PDT therapy. Targeting the RhoA/ROCK2/LIMK2/YAP pathway can significantly improve the efficacy of MPPa-PDT treatment for OS.
“… [247] 44 Gastric Simvastatin in vitro MKN45 and MGC803 cells Inhibits migration, invasion, proliferation, and induced apoptosis in gastric cancer cells by interfering with YAP and β-catenin activity. [206] 45 Gastric Simvastatin in vitro & Clinical AGS, ATCC CRL 1739 cells Statin reduces the incidence of gastric cancer by attenuating Helicobacter pylori CagA translocation [202] 46 Stomach Statin Clinical 17,737 statin users and 13,412 statin non-user The use of statin decreases the incidence of stomach cancer on hypercholesterolemic individuals. [252] 47 Blood (chronic myelogenous leukemia) Avasimibe, Imatinib in vitro & in vivo K562R (imatinib-resistant) Avasimibe sensitized K562R to imatinib [226] 48 Blood (lymphoblasts and myeloma cells) Lovastatin Simvastatin Cerivastatin Leverkusen, Atorvastatin in vitro Jurkat, CEM, IM9, U266 cell MCC-2 Statin induces mitochondrial apoptosis pathway in human T, B, and myeloma tumor cells causing cell death [200] 49 Blood (leukemia and lymphoma) Simvastatin, Atorvastatin, Rosuvastatin, Fluvastatin,Venetoclax in vitro, in vivo , & Clinical AML cells (OCI-AML2, OCI-AML3, MOLM13), DLBCL cells (OCI-LY8, SU-DHL4).C57BL/6 N mice Statin increases the pro-apoptotic activity of Venetoclax (B cell lymphoma-2 inhibitor) in primary leukemia and lymphoma cells [253] Fig.…”
Section: Targeting Cholesterol Metabolism For the Treatment Of Cancermentioning
confidence: 99%
“…Collectively, various studies reveal a positive effect of statin use in colon, breast, lung, liver, prostate, ovarian, gastric, blood, and pancreatic cancers [35 , 36 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206] . However, few reports suggest cancer-promoting or chemoresistant effect on statin treatment [207 , 208] , (209).…”
Section: Targeting Cholesterol Metabolism For the Treatment Of Cancermentioning
Highlights
Abnormality in blood cholesterol level is significantly correlated with risk of different cancers.
Majority of tumor tissue from cancer patient exhibits overexpression of LDLR and ACAT for supporting rapid cancer cell proliferation.
Alteration of the cholesterol metabolism in cancer cells hampers therapeutic response.
Targeting cholesterol metabolism for treatment of cancer with other conventional chemotherapeutic drugs appears to be beneficial.
“…Simvastatin increased LATS1 and phosphorylated YAP (S127) protein levels and decreased CYR61 expression, but the YAP protein level hardly changed. 65 In multiple cancer cell lines (including GC), this inhibitory effect on YAP may be achieved by inhibiting the activity of Rho through the MVA pathway, [64][65][66] and Rho can inhibit the…”
Section: Statinsmentioning
confidence: 99%
“…Simvastatin increased LATS1 and phosphorylated YAP (S127) protein levels and decreased CYR61 expression, but the YAP protein level hardly changed. 65 In multiple cancer cell lines (including GC), this inhibitory effect on YAP may be achieved by inhibiting the activity of Rho through the MVA pathway, 64–66 and Rho can inhibit the phosphorylation of YAP through LATS1/2. 67 These results indicate that the MVA pathway-Rho-YAP/TAZ axis may affect the progression and metastasis of GC.…”
Gastric cancer (GC) is one of the most common cancers globally, threatening global health. The deregulation of the Hippo signaling pathway has been discovered in GC and may be related to cancer development, proliferation, metastasis, and drug resistance. Yes-associated protein (YAP), as a downstream effector of the Hippo signaling pathway and a crucial cotranscription factor in the nucleus, is a promising and vital potential drug target for the treatment of GC. A series of drugs or compounds that inhibit YAP has been developed or confirmed. Therefore, this review will focus on summarizing the drugs and small-molecule inhibitors that have been reported to inhibit YAP and discuss the clinical prospects of YAP inhibitors in GC.
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