Gene regulatory networking reveals the molecular cue to lysophosphatidic acid-induced metabolic adaptations in ovarian cancer cells.

摘要: Extravasation and metastatic progression are two main reasons for the high mortality rate associated with cancer. The potential of cancer cells depends on a plethora metabolic challenges prevailing within tumor microenvironment. To achieve higher rates proliferation, reprogram their metabolism, increasing glycolysis biosynthetic activities. Just why this reprogramming predisposes towards increased oncogenesis remains elusive. accumulation myriad oncolipids in microenvironment has been shown to promote invasiveness cells, lysophosphatidic acid (LPA) being one such critical factor enriched ovarian patients. Cellular bioenergetic studies confirm that oxidative phosphorylation is suppressed long exposure LPA compared non-transformed epithelial cells. We sought uncover regulatory complexity underlying oncolipid-induced perturbation. Gene networking using RNA-Seq analysis identified oncogene ETS-1 as mediator LPA-induced alterations maintenance invasive phenotype. Moreover, receptor-2 specific PtdIns3K-AKT signaling induces its target matrix metalloproteases. Abrogation restores cellular bioenergetics reduced glycolysis, effect was reversed by presence LPA. Furthermore, status LPA-treated mimics hypoxia through induction hypoxia-inducible factor-1α, which found transactivate ets-1. Studies primary tumors generated syngeneic mice corroborated in vitro findings. Thus, our study highlights phenotypic changes induced pro-metastatic relationship between enhanced plasticity further illustrates role adaptation driver progression. These findings reveal predisposition new mechanism tumorigenesis propose inhibitors approach future management aggressive