Opposite functions of HIF-α isoforms in VEGF induction by TGF-β1 under non-hypoxic conditions

PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway

“…Expression plasmids encoding Cav1, Smad2, Smad3 and Smad4 were described previously. [10][11][12] shRNA vector cloning services were provided by Genolution. siRNA duplexes were synthesized by Dharmacon Research or Invitrogen using following sequences; 5'-GGC AUG UCA CAC AAC GCU AUC CGU U-3' (siPPARδ), 5'-ACA AGG AGA UCA GCG UGC ACG UCU U-3' (siPPARδ-2), 5'-GGG ACU GAG UAC ACC AAA UAC GAU A-3' (siSmad2), 5'-GAU GCA CUU GGU GUU GAC GUU-3' (siSmad3), 5'-GGU CAG CCA GCU ACU UAC CAU CAU A-3' (siSmad4), 5'-CCA GAA GGG ACA CAC AGU U-3' (siCav1), 5'-GCU CCC GGA GUU GUU GGA AAC UUU A-3' (siABCA1), 5'-CAU UCA CCA UCG AGU GCC AAA UGA A-3' (siTβRI), 5'-CAG CUG UAA UAG GAC UGC CCA UCC A-3' (siTβRII), 5'-CCC UGG AAG CCA UGA GAG AUG UCU A-3' (siERK1) and 5'-CAC CAU UCA AGU UCG ACA U-3' (siERK2).…”

“…9 We reported that tumor-producing TGF-β1 exerts mitogenic effects in prostate cancer cells through the activation of Ras-MAPK signaling and the induction of tumor-promoting genes, such as intereukin-6 and vascular endothelial growth factor, indicating that prostate cancers have a selective growth advantage by autocrine TGF-β1 production. [10][11][12] Therefore, TGF-β1 appears to play biphasic…”

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

“…In addition, other promising therapeutic strategies for eradicating the highly aggressive and chemoresistant PC cells may consist of targeting the deregulated metabolic pathways and specific signaling elements such as PI3K/Akt/mTOR, NF-κB, HIF-1α and 2α and MIC-1. These elements are induced under normoxic or hypoxic conditions and may provide critical functions for PC cell survival, invasion and metastasis; angiogenesis; and/or treatment resistance ( Figure 3) (29,46,47,129,133,140,(146)(147)(148)(211)(212)(213)(214)(215)(216)(217)(218). Consistent with this finding, the inhibition of glycolysis by using 2-deoxy-Dglucose (2-DG), alone or in combination with other anticancer agents such as pioglitazone, a microtubule disruptor, 2-methoxyoestradiol-3,17-O,O-bissulphamate (STX140) or metformin, which acts at least in part by inhibiting 2-DG-induced autophagy, has been shown to induce cytotoxic effects on the highly proliferative PC cells, including multicellular tumor spheroids from metastatic PC cells, and inhibit tumor growth in vivo (Figure 3) (147,148,212,213).…”

“…It has also been noted that the inhibition of glycolysis by either 2-DG or iodoacetate downregulated P-glycoprotein expression and inhibited the efflux of doxorubicin in multicellular tumor spheroids generated from metastatic and AI DU145 PC cells, suggesting that this therapeutic strategy may be effective for reversing the multidrug resistance phenotype of PC cells (146). In this regard, the downregulation of COX-2, HIF-1α and/or HIF-2α expression levels or activities also constitute other potential strategies to inhibit glycolysis, tumor angiogenesis and eradicate invasive and metastatic PC cells (Figure 3) (29,46,47,133,140,(214)(215)(216). Consistently, it has been reported that the targeting of HIF-1α and/or HIF-2α in PC cells by RNA silencing or using a specific inhibitor of HIF-1α, PX-478 (S-2-amino-3-[4′-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride), or inhibitor of the proteasomal degradation of HIF-1α and/or HIF-2α such as ascorbic acid or zinc inhibited their invasive ability in vitro and tumor formation and lung metastases in vivo (Figure 3) (47,206,219).…”

“…It has been shown that the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/β-catenin, hyaluronan (HA)/CD44, transforming growth factor (TGF)-β/ TGF-βR receptors and stromal cell-derived factor-1 (SDF-1)/ CXC chemokine receptor 4 (CXCR4) frequently occurs during PC progression to locally invasive and metastatic CRPCs (5,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). These tumorigenic cascades can account for the sustained growth, survival, invasion, metastases and treatment resistance of PC cells.…”