Regulations of Tumor Microenvironment by Prostaglandins.

Prostaglandins, the bioactive lipids generated from the metabolism of arachidonic acid through cyclooxygenases, have potent effects on many constituents of tumor microenvironments. In this review, we will describe the formation and activities of prostaglandins in the context of the tumor microenvironment. We will discuss the regulation of cancer-associated fibroblasts and immune constituents by prostaglandins and their roles in immune escapes during tumor progression.

Sensing plasma membrane pore formation induces chemokine production in survivors of regulated necrosis.

Although overwhelming plasma membrane integrity loss leads to cell lysis and necrosis, cells can tolerate a limited level of plasma membrane damage, undergo ESCRT-III-mediated repair, and survive. Here, we find that cells which undergo limited plasma membrane damage from the pore-forming actions of MLKL, GSDMD, perforin, or detergents experience local activation of PKCs through Ca influx at the damage sites. S660-phosphorylated PKCs subsequently activate the TAK1/IKKs axis and RelA/Cux1 complex to trigger chemokine expressions.

Blockade of leukemia inhibitory factor as a therapeutic approach to KRAS driven pancreatic cancer.

KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, Kras-driven, PDAC mouse model.

K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling.

K-Ras and H-Ras share identical effectors and have similar properties; however, the high degree of tumor-type specificity associated with K-Ras and H-Ras mutations suggests that they have unique roles in oncogenesis. Here, we report that oncogenic K-Ras, but not H-Ras, suppresses non-canonical Wnt/Ca(2+) signaling, an effect that contributes strongly to its tumorigenic properties. K-Ras does this by binding to calmodulin and so reducing CaMKii activity and expression of Fzd8.

Impairment of mitochondrial respiration in mouse fibroblasts by oncogenic H-RAS(Q61L).

A common metabolic change in cancer is the acquisition of glycolytic phenotypes. Increased expression of glycolytic enzymes is considered as one contributing factor. The role of mitochondrial defects in acquisition of glycolytic phenotypes has been postulated but remains controversial.

Downregulation of vascular endothelial growth factor and induction of tumor dormancy by 15-lipoxygenase-2 in prostate cancer.

The enzyme 15-lipoxygenase-2 (15-LOX-2) utilizes arachidonic acid, a polyunsaturated fatty acid, to synthesize 15(S)-hydroxyeicosatetraenoic acid. Abundantly expressed in normal prostate epithelium but frequently suppressed in the cancerous tissues, 15-LOX-2 has been suggested as a functional suppressor of prostate cancer, but the mechanism(s) involved remains unknown. To study the functional role of 15-LOX-2 in prostate cancer, we expressed 15-LOX-2 as a fusion protein with GFP in DU145 and PC-3 cells and found that 15-LOX-2 increased cell cycle arrest at G0/G1 phase.

Thromboxane A2 receptors in prostate carcinoma: expression and its role in regulating cell motility via small GTPase Rho.

Thromboxane A(2) (TxA(2)) is a prostanoid formed by thromboxane synthase using the cyclooxygenase product prostaglandin H(2) as the substrate. Previously, increased expression of thromboxane synthase was found in prostate tumors, and tumor cell motility was attenuated by inhibitors of thromboxane synthase. This study was undertaken to elucidate how tumor motility is regulated by TxA(2).

Role of Rho GTPases in breast cancer.

Small GTPase Rho signaling pathways regulate the growth, motility, invasion and metastasis of breast cancer cells. Aberrant Rho signaling, as results from alterations in the levels of Rho GTPase proteins, the status of activation, and the abundance of effector proteins, is found in breast cancers. Alterations of Rho signaling particularly impact the cytoskeleton, whose organization and reorganization underpin the motility of breast cancer cells during the invasive growth and metastasis of breast cancer.

Human pregnane X receptor and resistance to chemotherapy in prostate cancer.

Resistance to chemotherapy is a significant barrier to the effective management of prostate cancer. Human pregnane X receptor (hPXR), an orphan nuclear receptor known for its activation by many important clinical drugs, interacts with many cellular signaling pathways during carcinogenesis and is a major transcription factor regulating the expression of drug metabolism enzymes, including transporters. It is unknown whether hPXR is a determinant of drug resistance in prostate cancer.

Cyclooxygenases, prostanoids, and tumor progression.

In response to various growth factors, hormones or cytokines, arachidonic acid can be mobilized from phospholipids pools and converted to bioactive eicosanoids through cyclooxygenase (COX), lipoxygenase (LOX) or P-450 epoxygenase pathway. The COX pathway generates five major prostanoids (prostaglandin D(2), prostaglandin E(2), prostaglandin F(2)alpha, prostaglandin I(2) and thromboxane A(2)) that play important roles in diverse biological processes. Studies suggest that different prostanoids and their own synthase can play distinct roles in tumor progression and cancer metastasis.