Oncogenes strike a balance between cellular growth and homeostasis

Abstract

Altered tumor cell metabolism is now firmly established as a hallmark of human cancer. Downstream of oncogenic events, metabolism is re-wired to support cellular energetics and supply the building blocks for biomass. Rapid, uncontrolled proliferation results in tumor growth beyond the reach of existing vasculature and triggers cellular adaptations to overcome limiting nutrient and oxygen delivery. However, oncogenic activation and metabolic re-programming also elicit cell intrinsic stresses, independent of the tumor microenvironment. To ensure metabolic robustness and stress resistance, pro-growth signals downstream of oncogene activation or tumor suppressor loss simultaneously activate homeostatic processes. Here, we summarize recent literature describing the adaptive mechanisms co-opted by common oncogenes, including mTOR, MYC, and RAS. Recurrent themes in our review include: (1) coordination of oncogene-induced changes in protein and lipid metabolism to sustain endoplasmic reticulum homeostasis, (2) maintenance of mitochondrial functional capacity to support anabolic metabolism, (3) adaptations to sustain intracellular metabolite concentrations required for growth, and (4) prevention of oxidative stress. We also include a discussion of the hypoxia inducible factors (HIFs) and the AMP-dependent protein kinase (AMPK)--stress sensors that are co-opted to support tumor growth. Ultimately, an understanding of the adaptations required downstream of specific oncogenes could reveal targetable metabolic vulnerabilities.

Keywords: AMPK; Autophagy; Cancer metabolism; ER stress; Hypoxia inducible factors; Stress response.

Figure 1. mTORC1 driven adaptations to support tumor growth

Activation of protein synthesis downstream of mTORC1 supports tumor progression, but also consumes amino acids at a rapid rate. To maintain amino acid concentrations required to sustain protein synthesis and anabolic metabolism, mTORC1 activates NRF1-dependepent proteasome biosynthesis (A). Another potential function of enhanced proteasome activity downstream of mTORC1 is maintenance of protein quality control (B), as proteasome dependent ER associated protein degradation (ERAD) is a part of the UPR. Increased protein synthesis also enhances ER stress (C). To expand the ER membrane and accommodate increased protein load, mTORC1 activates SREBP-dependent lipogenic gene expression. In particular, synthesis of unsaturated lipid by SCD1 is crucial to maintain ER lipid homeostasis and prevent ER stress (D). Functional outputs of tumor cell adaptations are shown in red. Question marks denote hypothesized mechanisms that have not been directly tested.

Figure 2. MYC driven adaptations to support tumor growth

Activation of protein synthesis downstream of MYC supports tumor progression. An increase in ER protein load triggers the UPR (A), which limits ER stress by multiple mechanisms. Activation of PERK facilitates cytoprotective autophagy (B). IRE-1α signaling upregulates the NAD+ dependent histone deacetylase SIRT7 (C), which represses MYC-dependent transcription of ribosomal genes and limits protein synthesis rate to prevent ER stress. MYC activates lipogenic gene expression by upregulating MondoA-dependent lipid synthesis (D), which is required for viability in MYC-activated cells. A potential mechanism involves maintenance of ER lipid homeostasis to accommodate increased protein load and limit ER stress (E). MYC drives glutamine uptake and metabolism to support anabolic processes. (F). This process, termed glutamine-dependent anaplerosis, requires mitochondrial metabolism. MYC activates an ARK5-AMPK pathway to maintain mitochondrial function (G). ARK5 ablation is synthetically lethal to MYC activated cells. Functional outputs of tumor cell adaptations are shown in red. Question marks denote hypothesized mechanisms that have not been directly tested.

Figure 3. RAS driven adaptations to support tumor growth

A well-recognized feature of RAS activated cells is increased levels of mitochondrial reactive oxygen species (A). While low levels of ROS promote tumor growth, RAS transformed cells must engage adaptations to prevent excessive oxidative damage. RAS drives glutamine-dependent NADPH generation via aspartate amino transferase (GOT1) and malic enzyme 1 (ME1). NADPH generated from this pathway is required to for redox balance in RAS transformed cells (B). RAS also stimulates high rates of basal autophagy (C), which are required to maintain mitochondrial function and limit oxidative stress. To sustain intracellular amino acid concentrations, such as glutamine, RAS transformed cells engage in macropinocytosis of extracellular protein (D). Note that both autophagy and macropinocytosis-dependent nutrient acquisition require lysosome function, revealing a potential vulnerability of RAS transformed cells. Functional outputs of tumor cell adaptations are shown in red.