Abstract
The KRAS proto-oncogene plays a key role in the development of many human tumors and is commonly activated by somatic mutation or signaling through specific growth factor receptors. However, the interaction between the micro-environment and K-ras activity has not been defined. Hypoxia invariably develops as tumors outgrow their supply of oxygen. A series of well-orchestrated cellular adaptations occur that stimulate angiogenesis and enhance survival of the tumor in hypoxic conditions. Our previous studies demonstrated that mutant KRAS alleles can interact with hypoxia to induce vascular endothelial growth factor (VEGF) in colon cancer. We sought to determine whether similar hypoxic responses are also present in tumors without a KRAS mutation. Hypoxia consistently increased the levels of activated, GTP-bound K-ras in colon cancer cell lines with a wild-type KRAS gene, and this depended upon the activation of c-Src. Inhibition of c-Src by PP2 treatment or siRNA knockdown blocked the hypoxic activation of K-ras. This activation of K-ras did not depend upon EGFR and resulted in the phosphorylation of Akt and induction of VEGF expression. In addition, activation of K-ras significantly blocked apoptosis in hypoxic conditions. These studies reveal a unique adaptive mechanism in hypoxia that activates K-ras signaling in the absence of a mutant KRAS oncogene.
Highlights
The development of tissue hypoxia is characteristically observed as malignant tumors rapidly increase in size
Previous studies have demonstrated that hypoxia-inducible factor (HIF)-independent mechanisms can induce vascular endothelial growth factor (VEGF) in hypoxia, and oncogenic K-ras plays a key role in this process [2,3,4]
Hypoxic activation of K-Ras in colon cancer cells To determine whether hypoxia activates Ras, we measured
Summary
The development of tissue hypoxia is characteristically observed as malignant tumors rapidly increase in size. Previous studies have demonstrated that HIF-independent mechanisms can induce VEGF in hypoxia, and oncogenic K-ras plays a key role in this process [2,3,4]. K-ras is a small GTPase that cycles between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound conformations (Ras-GDP and Ras-GTP, respectively) [5] It serves as a signal switch molecule that couples receptor activation by specific growth factors with downstream effector pathways including the Ras-MEK-ERK and phosphatidylinositol 3-kinase (PI3K)-Akt cascades that control multiple cellular responses. Previous studies have demonstrated a strong synergistic interaction between hypoxia and mutant K-ras in the regulation of multiple target genes including vascular endothelial growth factor (VEGF), IL-8, and osteopontin [2,8,9]. Fewer than 50% of colon tumors harbor KRAS mutations, and the relationship between Ras signaling and hypoxia in tumors with wild-type KRAS remains undefined
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