Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs

Lim, Maegan Miang Kee; Wee, Jonathan Wei Kiat; Soong, Jen Chi; Chua, Damien; Tan, Wei; Lizwan, Marco; Li, Yinliang; Teo, Ziqiang; Goh, Wilson Wen Bin; Zhu, Pengcheng; Tan, Nguan Soon

doi:10.1186/s12943-018-0904-z

Cited by 18 publications

(22 citation statements)

References 10 publications

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“…A previous study investigating protein-protein interactions, using bioinformatics analysis, indicated that the expression of ATP-dependent transporters and Bcl-xL was mainly induced by the activation of transcription factors, such as NF-κB and the upstream kinase pathway ( 18 ). To further explore the molecular mechanism by which ANGPTL4 induced the upregulation of intracellular ATP-dependent transporters and Bcl-xL, a series of molecular biological experiments were performed for verification.…”

Section: Resultsmentioning

confidence: 99%

Adipocytes induce the resistance of ovarian cancer to carboplatin through ANGPTL4

2020

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The resistance of cancer cells to carboplatin restricts their efficacy in the clinical setting, and a solution to reverse the resistance is urgently required for the treatment of ovarian cancer. An increasing number of studies have found associations between obesity and the incidence, and mortality rates of female cancer. However, the association between adipocytes and the resistance of ovarian cancer has rarely been reported. Based on this, the present study first revealed the inductive effect of adipocytes on the resistance of ovarian cancer to carboplatin using in vivo and in vitro experiments. Subsequently, it was identified that the angiopoietin-like 4 (ANGPTL4) secreted by adipocytes played a vital role in the resistance of ovarian cancer using bioinformatics analysis, cellular and molecular biological experiments, as well as forward and backward validation. The glycosylated ANGPTL4 protein could bind with integrin α5β1 on the surface of ovarian cancer cells; following which, it could activate the c-myc/NF-κB pathway and stimulate the expression of the antiapoptotic protein Bcl-xL, as well as the ABC transporter family members ABCB1, ABCC1 and ABCG2. Thus, inducing the resistance of ovarian cancer to carboplatin. In conclusion, targeting the adipocyte-derived ANGPTL4 combined with the application of carboplatin contributes to the clinical treatment for ovarian cancer.

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Section: Resultsmentioning

confidence: 99%

Adipocytes induce the resistance of ovarian cancer to carboplatin through ANGPTL4

2020

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“…One of the common reasons that have been a significant impediment to the success of cancer pharmacotherapies is the overexpression of ATP-binding cassette (ABC) efflux transporters in cancer cells. Recent studies have established that angiopoietin-like 4 (ANGPTL4) protein plays a pivotal role in the metastatic distribution of cancer cells and boosts MDR in the cancerous cell during the EMT process by transcriptionally upregulating the ABC transporters expression via the Myc and NF-κB signaling pathways [ 204 ]. It has also been observed that ANGPTL4 increases ABC transporter activity, which results in pushing anticancer drugs out of cells, which causes chemotherapy failure.…”

Section: Clinical Evidence For the Actin Cytoskeleton In Emt And Therapeutic Implicationsmentioning

confidence: 99%

Cytoskeletal Dynamics in Epithelial-Mesenchymal Transition: Insights into Therapeutic Targets for Cancer Metastasis

Datta

Deng

Gopal

et al. 2021

Cancers

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In cancer cells, a vital cellular process during metastasis is the transformation of epithelial cells towards motile mesenchymal cells called the epithelial to mesenchymal transition (EMT). The cytoskeleton is an active network of three intracellular filaments: actin cytoskeleton, microtubules, and intermediate filaments. These filaments play a central role in the structural design and cell behavior and are necessary for EMT. During EMT, epithelial cells undergo a cellular transformation as manifested by cell elongation, migration, and invasion, coordinated by actin cytoskeleton reorganization. The actin cytoskeleton is an extremely dynamic structure, controlled by a balance of assembly and disassembly of actin filaments. Actin-binding proteins regulate the process of actin polymerization and depolymerization. Microtubule reorganization also plays an important role in cell migration and polarization. Intermediate filaments are rearranged, switching to a vimentin-rich network, and this protein is used as a marker for a mesenchymal cell. Hence, targeting EMT by regulating the activities of their key components may be a potential solution to metastasis. This review summarizes the research done on the physiological functions of the cytoskeleton, its role in the EMT process, and its effect on multidrug-resistant (MDR) cancer cells—highlight some future perspectives in cancer therapy by targeting cytoskeleton.

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“…The real-time qPCR and immunoblot analyses were performed as previously described [50,51]. The sequences of primers for qPCR are in Table S2.…”

Section: Real-time Pcr (Qpcr) and Immunoblot Analysesmentioning

confidence: 99%

PPARβ/δ Agonism Upregulates Forkhead Box A2 to Reduce Inflammation in C2C12 Myoblasts and in Skeletal Muscle

Phua

Tan

Yip

et al. 2020

IJMS

Self Cite

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Daily activities expose muscles to innumerable impacts, causing accumulated tissue damage and inflammation that impairs muscle recovery and function, yet the mechanism modulating the inflammatory response in muscles remains unclear. Our study suggests that Forkhead box A2 (FoxA2), a pioneer transcription factor, has a predominant role in the inflammatory response during skeletal muscle injury. FoxA2 expression in skeletal muscle is upregulated by fatty acids and peroxisome proliferator-activated receptors (PPARs) but is refractory to insulin and glucocorticoids. Using PPARβ/δ agonist GW501516 upregulates FoxA2, which in turn, attenuates the production of proinflammatory cytokines and reduces the infiltration of CD45+ immune cells in two mouse models of muscle inflammation, systemic LPS and intramuscular injection of carrageenan, which mimic localized exercise-induced inflammation. This reduced local inflammatory response limits tissue damage and restores muscle tetanic contraction. In line with these results, a deficiency in either PPARβ/δ or FoxA2 diminishes the action of the PPARβ/δ agonist GW501516 to suppress an aggravated inflammatory response. Our study suggests that FoxA2 in skeletal muscle helps maintain homeostasis, acting as a gatekeeper to maintain key inflammation parameters at the desired level upon injury. Therefore, it is conceivable that certain myositis disorders or other forms of painful musculoskeletal diseases may benefit from approaches that increase FoxA2 activity in skeletal muscle.

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Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs

Cited by 18 publications

References 10 publications

Adipocytes induce the resistance of ovarian cancer to carboplatin through ANGPTL4

Adipocytes induce the resistance of ovarian cancer to carboplatin through ANGPTL4

Cytoskeletal Dynamics in Epithelial-Mesenchymal Transition: Insights into Therapeutic Targets for Cancer Metastasis

PPARβ/δ Agonism Upregulates Forkhead Box A2 to Reduce Inflammation in C2C12 Myoblasts and in Skeletal Muscle

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