REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase

Abstract

Cancer cells frequently evade apoptosis during tumorigenesis by acquiring mutations in apoptotic regulators. Chronic activation of the PI 3-kinase-Akt pathway through loss of the tumor suppressor PTEN is one mechanism by which these cells can gain increased protection against apoptosis. We report here that REDD1 (RTP801) can act as a transcriptional downstream target of PI 3-kinase signaling in human prostate cancer cells (PC-3). REDD1 expression is markedly reduced in PC-3 cells treated with LY294002 (LY) or Rapamycin and strongly induced under hypoxic conditions in a hypoxiainducible factor-1 (HIF-1)-dependent manner. Loss of function studies employing antisense molecules or RNA interference indicate that REDD1 is essential for invasive growth of prostate cancer cells in vitro and in vivo. Reduced REDD1 levels can sensitize cells towards apoptosis, whereas elevated levels of REDD1 induced by hypoxia or overexpression desensitize cells to apoptotic stimuli. Taken together our data designate REDD1 as a novel target for therapeutic intervention in prostate cancer.

REDD1 is required for RAS-mediated transformation of human ovarian epithelial cells

“…On the other hand, REDD1 was found to play an important role in the growth of prostate cancer cells (PC-3) in vitro and in vivo reported by Schwarzer et al Reduced REDD1 levels could sensitize cells to apoptosis, whereas elevated levels of REDD1 induced by hypoxia or overexpression desensitized cells to apoptotic stimuli. 13 It was also shown in another study that mice with the BRCA1 mutation and p53 haploid loss exhibited increased expression of REDD1 and had high cancer susceptibility. 14 As reported by An SJ and colleagues, REDD1 also was found to be overexpressed in carcinoma induced by BPDE-transformed 16HBE cells (16HBE-C cells).…”

Quantitative Lys-ϵ-Gly-Gly (diGly) Proteomics Coupled with Inducible RNAi Reveals Ubiquitin-mediated Proteolysis of DNA Damage-inducible Transcript 4 (DDIT4) by the E3 Ligase HUWE1

“…In cancer cells, DDIT4 function appears to be context-dependent. In some cancer cell lines and mouse models, DDIT4 appears to act as an oncogene in a prosurvival role in part by blocking apoptosis (71,72), whereas in other cell-based and in vivo experiments, it functions as a tumor suppressor (67,73). When considering whether HUWE1 is an appropriate target for cancer or other disease indications, it should be noted that inhibition of HUWE1 with a concomitant increase in DDIT4 expression may have beneficial or detrimental effects for the therapeutic strategy.…”

Metabolic consideration of epiphyseal growth: Survival responses in a taxing environment

“…In addition to hypoxic induction, REDD-1 can be induced by either ATP depletion or direct activation of the AMP-activated protein kinase (AMPK). These studies have shown that REDD-1 is a critical transducer of the cellular response to energy depletion and hypoxia through the mTOR pathway (Fig 3) [27][28][29].…”