Prolyl Hydroxylase 3 Attenuates MCL-1–Mediated ATP Production to Suppress the Metastatic Potential of Colorectal Cancer Cells

Abstract

Hypoxia is a common feature of solid tumors. Prolyl hydroxylase enzymes (PHD1-3) are molecular oxygen sensors that regulate hypoxia-inducible factor activity, but their functions in metastatic disease remain unclear. Here, we assessed the significance of PHD enzymes during the metastatic spread of colorectal cancer. PHD expression analysis in 124 colorectal cancer patients revealed that reduced tumoral expression of PHD3 correlated with increased frequency of distant metastases and poor outcome. Tumorigenicity and metastatic potential of colorectal tumor cells over and underexpressing PHD3 were investigated in orthotopic and heterotopic tumor models. PHD3 overexpression in a syngeneic tumor model resulted in fewer liver metastases, whereas PHD3 knockdown induced tumor spread. The migration of PHD3-overexpressing tumor cells was also attenuated in vitro. Conversely, migratory potential and colony formation were enhanced in PHD3-deficient cells, and this phenotype was associated with enhanced mitochondrial ATP production. Furthermore, the effects of PHD3 deficiency were accompanied by increased mitochondrial expression of the BCL-2 family member, member myeloid cell leukemia sequence 1 (MCL-1), and could be reversed by simultaneous inhibition of MCL-1. MCL-1 protein expression was likewise enhanced in human colorectal tumors expressing low levels of PHD3. Therefore, we demonstrate that downregulation of PHD3 augments metastatic spread in human colorectal cancer and identify MCL-1 as a novel downstream effector of oxygen sensing. Importantly, these findings offer new insight into the possible, context-specific deleterious effects of pharmacologic PHD inhibition. Cancer Res; 76(8); 2219-30. Ó2016 AACR.

Coexisting genomic aberrations associated with lymph node metastasis in breast cancer

“…MCL1 is a prosurvival gene and a member of the BCL2 family, which governs the intrinsic apoptotic pathway (33) and has been shown to be highly expressed in some breast cancers, playing an important role in patient response to antitubulin chemotherapeutics (34). MCL1 expression has been associated with metastasis in colorectal (35), gastric (36,37), and breast cancers (38)(39)(40). Our study also identified aberrations of several other genes or chromosome regions that were enriched in ER + breast cancer patients with versus those without lymph node metastasis, including gains of chr12q and chr20q and losses of chr1p and chr9p, most of whose copy number alteration (CNA) have not previously been associated with breast cancer metastasis ( Figure 6B).…”

Restoration of the prolyl-hydroxylase domain protein-3 oxygen-sensing mechanism is responsible for regulation of HIF2α expression and induction of sensitivity of myeloma cells to hypoxia-mediated apoptosis

“…PHD3 is a presumptive tumor suppressor gene that is distinct from the other PHD isoforms whose expression varies between different cell types and oxygen concentrations. PHD3 promotes neuronal apoptosis [ 10 ], and downregulation of PHD3 expression is frequently observed in glioblastoma [ 11 , 12 ], colorectal cancer [ 13 ], soft tissue sarcomas [ 14 ] and breast cancer [ 15 ]. In some tumors, PHD3 expression is lost during the process of tumor de-differentiation and metastasis [ 13 , 16 ].…”

Prolyl hydroxylase domain protein 3 and asparaginyl hydroxylase factor inhibiting HIF-1 levels are predictive of tumoral behavior and prognosis in hepatocellular carcinoma

“…To our opinion, this diversity of PHD3 expression might be at least partly due to the tissue heterogeneity. It is also worth mention that several independent clinical trials on CRC not only indicated a decreased expression of PHD3 and FIH, but also revealed their association with higher tumor grade and metastasis [27, 45, 46, 49, 50]. …”

“…Several studies further provided compelling evidences to elucidate the effective of PHD3 in tumorigenesis and metastasis. It could inhibit the tumor migratory potential both in vivo and in vitro by reducing matrix metalloproteinases production, blocking the colony formation, decrease the mitochondrial ATP generation, suppress the beta-catenin/T-cell factor signaling and inhibit IKKβ/NF-κB signaling, independent of its hydroxylase activity [48–50]. On the other hand, activity of PHD3 to induce apoptosis through HIF-1-dependent, or independent pathway by activation of caspase-3 also contributed to the above correlation [52, 53].…”