RESUMEN
Solid tumours often endure nutrient insufficiency during progression. How tumour cells adapt to temporal and spatial nutrient insufficiency remains unclear. We previously identified STC2 as one of the most upregulated genes in cells exposed to nutrient insufficiency by transcriptome screening, indicating the potential of STC2 in cellular adaptation to nutrient insufficiency. However, the molecular mechanisms underlying STC2 induction by nutrient insufficiency and subsequent adaptation remain elusive. Here, we report that STC2 protein is dramatically increased and secreted into the culture media by Gln-/Glc-deprivation. STC2 promoter contains cis-elements that are activated by ATF4 and p65/RelA, two transcription factors activated by a variety of cellular stress. Biologically, STC2 induction and secretion promote cell survival but attenuate cell proliferation during nutrient insufficiency, thus switching the priority of cancer cells from proliferation to survival. Loss of STC2 impairs tumour growth by inducing both apoptosis and necrosis in mouse xenografts. Mechanistically, under nutrient insufficient conditions, cells have increased levels of reactive oxygen species (ROS), and lack of STC2 further elevates ROS levels that lead to increased apoptosis. RNA-Seq analyses reveal STC2 induction suppresses the expression of monoamine oxidase B (MAOB), a mitochondrial membrane enzyme that produces ROS. Moreover, a negative correlation between STC2 and MAOB levels is also identified in human tumour samples. Importantly, the administration of recombinant STC2 to the culture media effectively suppresses MAOB expression as well as apoptosis, suggesting STC2 functions in an autocrine/paracrine manner. Taken together, our findings indicate that nutrient insufficiency induces STC2 expression, which in turn governs the adaptation of cancer cells to nutrient insufficiency through the maintenance of redox homeostasis, highlighting the potential of STC2 as a therapeutic target for cancer treatment.
RESUMEN
Each individual has a unique and interacting set of genetic, lifestyle, and environmental factors that are reflected in their physical exam and laboratory biomarkers and significantly impact their experience of health. Patterns of nutrient deficiency signs and biomarker levels below health-promoting thresholds have been identified in national nutrition surveys. However, identifying these patterns remains a challenge in clinical medicine for many reasons, including clinician training and education, clinical time restraints, and the belief that these signs are both rare and recognizable only in cases of severe nutritional deficiencies. With an increased interest in prevention and limited resources for comprehensive diagnostic evaluations, a functional nutrition evaluation may augment patient-centered screening evaluations and personalized wellness programs. During LIFEHOUSE, we have documented physical exam, anthropometric, and biomarker findings that may increase the recognition of these wellness-challenging patterns in a population of 369 adult employees working in two occupational areas: administrative/sales and manufacturing/warehouse. Distinct and significant physical exam differences and constellations of biomarker abnormalities were identified. We present these patterns of physical exam findings, anthropometrics, and advanced biomarkers to assist clinicians in diagnostic and therapeutic interventions that may stem the loss of function that precedes the development of the non-communicable chronic diseases of aging.