Protein Kinase A Activation Promotes Cancer Cell Resistance to Glucose Starvation and Anoikis

Abstract

Cancer cells often rely on glycolysis to obtain energy and support anabolic growth. Several studies showed that glycolytic cells are susceptible to cell death when subjected to low glucose availability or to lack of glucose. However, some cancer cells, including glycolytic ones, can efficiently acquire higher tolerance to glucose depletion, leading to their survival and aggressiveness. Although increased resistance to glucose starvation has been shown to be a consequence of signaling pathways and compensatory metabolic routes activation, the full repertoire of the underlying molecular alterations remain elusive. Using omics and computational analyses, we found that cyclic adenosine monophosphate-Protein Kinase A (cAMP-PKA) axis activation is fundamental for cancer cell resistance to glucose starvation and anoikis. Notably, here we show that such a PKA-dependent survival is mediated by parallel activation of autophagy and glutamine utilization that in concert concur to attenuate the endoplasmic reticulum (ER) stress and to sustain cell anabolism. Indeed, the inhibition of PKA-mediated autophagy or glutamine metabolism increased the level of cell death, suggesting that the induction of autophagy and metabolic rewiring by PKA is important for cancer cellular survival under glucose starvation. Importantly, both processes actively participate to cancer cell survival mediated by suspension-activated PKA as well. In addition we identify also a PKA/Src mechanism capable to protect cancer cells from anoikis. Our results reveal for the first time the role of the versatile PKA in cancer cells survival under chronic glucose starvation and anoikis and may be a novel potential target for cancer treatment.

Differences of basic and induced autophagic activity between K562 and K562/ADM cells

“…A report has described that activation of autophagy is critical for cancer cellular survival under nutrient starvation (39). Another report also demonstrates that CD133-positive glioma cells exhibit higher survival under starvation conditions, which depends on induction of autophagy (40).…”

Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein 1

“…HMM cells used a distinct metabolism to generate energy compared to normal mesothelial cells and glucose starvation promoted more severe metabolic alterations . Therefore, energy‐deficient cancer cells survived through PKA over activated metabolism alteration . Surviving HMM cells under glucose starvation exhibited metformin resistance.…”

“…30,31 Therefore, energy-deficient cancer cells survived through PKA over activated metabolism alteration. 32 Surviving HMM cells under glucose starvation exhibited metformin resistance. The viability of HMM cells cultured under glucose starvation with metformin was unchanged and apoptosis was decreased compared to those of cells cultured in complete medium.…”

Inhibitory role of AMP‑activated protein kinase in necroptosis of HCT116 colon cancer cells with p53 null mutation under nutrient starvation

“…Unlike normal cells, cancer cells require unusually large amounts of nutrients to support their uncontrolled growth and proliferation; therefore, they are more easily exposed to severe nutrient deficiencies compared with normal cells. However, many cancer cells develop tolerance and overcome nutrient limitations by increasing nutrient uptake through alterations in metabolic signaling pathways or by activating angiogenesis (11)(12)(13)(14)(15)(16). Therefore, it is important to elucidate these mechanisms, in order to develop novel therapeutic approaches.…”