Autophagy, Stress, and Cancer Metabolism: What Doesn't Kill You Makes You Stronger

Abstract

Altered metabolism is a hallmark of cancer. Oncogenic events that lead to cancerous states reorganize metabolic pathways to increase nutrient uptake, which promotes biosynthetic capabilities and cell-autonomous behavior. Increased biosynthesis dictates metabolic demand for ATP, building blocks, and reducing equivalents, rendering cancer cells metabolically in a perpetually hungry state. Moreover, most chemotherapy agents induce acute metabolic stress that cancer cells must overcome for their survival. These metabolic stress cues in cancer cells can activate and cause dependence on the self-cannibalization mechanism of macroautophagy (autophagy hereafter) for the lysosomal turnover and recycling of organelles and proteins for energy and stress survival. For example, activating mutations in Ras or Ras-effector pathways induce autophagy, and cancer cell lines with Ras activation show elevated levels of basal autophagy that is essential for starvation survival and tumor growth. The metabolic implications of this are profound and multifaceted. First, autophagy-mediated degradation and recycling of cellular substrates can support metabolism and promote survival and tumor growth. Second, acute autophagy activation in response to cancer therapy can potentially lead to refractory tumors resistant to conventional chemotherapy. For example, a specific form of autophagy that targets mitochondria (mitophagy) may also function to promote cell survival by the clearance of damaged mitochondria that are potential sources of reactive oxygen species (ROS). These point to the possibility that autophagy is a unique metabolic need, important for survival as well as therapy resistance in cancer cells. Targeting autophagy in single-agent therapy to sensitize aggressive cancers that are dependent on autophagy for survival or in combination with therapeutic agents that induce autophagy as a resistance mechanism may be an effective therapeutic strategy to treat cancer.

Autophagy at the crossroads of catabolism and anabolism

“…The contributions of autophagy to tumour metabolism have been recently reviewed [56][57][58] . Similar to normal cells, tumour cell autophagy recycles macromolecules for amino acid synthesis and mitochondrial metabolism to support growth and survival 59 .…”

AMP-activated protein kinase (AMPK) beyond metabolism

“…52,99 Stress-induced initiation of autophagy requires activation of the Unc-51-like kinase (ULK) complex, which consists of ULK1, ULK2, Atg13, and FIP200, and is tightly regulated by AMPK and mTOR. 100 Starvation and stress-activated AMPK phosphorylates ULK1 on Ser317 and Ser777 to initiate autophagy. Conversely, under nutrient-depleted conditions, mTORC1 phosphorylates ULK1 on Ser757, which displaces the interaction of AMPK with ULK1 and suppresses autophagy.…”

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

“…[32][33][34] Two autophagy inducers, LAPTM4B, a lysosomal transmembrane glycoprotein required for lysosome function and autophagosome maturation, and BNIP3, a BH3 domain-containing protein that can induce both apoptosis and hypoxia-mediated mitophagy, showed increased mRNA in multiple tumor types. Upregulated LAPTM4B mRNA and protein levels have been documented in multiple cancers and cell lines, where they correlate with pathological grade and prognosis in vivo and promote proliferation, migration, invasion, and drug resistance in vitro.…”