Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy

Fasting reduces glucose levels and protects mice against chemotoxicity, yet drugs that promote hyperglycemia are widely used in cancer treatment. Here, we show that dexamethasone (Dexa) and rapamycin (Rapa), commonly administered to cancer patients, elevate glucose and sensitize cardiomyocytes and mice to the cancer drug doxorubicin (DXR). Such toxicity can be reversed by reducing circulating glucose levels by fasting or insulin. Furthermore, glucose injections alone reversed the fasting-dependent protection against DXR in mice, indicating that elevated glucose mediates, at least in part, the sensitizing effects of rapamycin and dexamethasone. In yeast, glucose activates protein kinase A (PKA) to accelerate aging by inhibiting transcription factors Msn2/4. Here, we show that fasting or glucose restriction (GR) regulate PKA and AMP-activated protein kinase (AMPK) to protect against DXR in part by activating the mammalian Msn2/4 ortholog early growth response protein 1 (EGR1). Increased expression of the EGR1-regulated cardioprotective peptides atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in heart tissue may also contribute to DXR resistance. Our findings suggest the existence of a glucose–PKA pathway that inactivates conserved zinc finger stress-resistance transcription factors to sensitize cells to toxins conserved from yeast to mammals. Our findings also describe a toxic role for drugs widely used in cancer treatment that promote hyperglycemia and identify dietary interventions that reverse these effects.Author summary: Fasting can selectively protect normal cells against the deleterious side effects of chemotherapy while sensitizing cancer cells to therapy. This is, in part, due to the reallocation of energy from growth to protection in normal cells but not cancer cells in response to reduced nutrient availability. Because glucose sensitizes yeast cells to stress and considering that several widely used drugs that increase glucose levels are administered in combination with chemotherapy, we tested the role of glucose reduction on the sensitivity of normal cells and mice to the chemotherapy drug doxorubicin (DXR). We show that fasting or glucose restriction (GR) reduce protein kinase A (PKA) activation and increase AMP-activated protein kinase (AMPK) activity. These signal transduction changes cause the activation of the conserved zinc finger stress-resistance transcription factor early growth response protein 1 (EGR1) (Msn2/4 in yeast) to protect cardiomyocytes from doxorubicin toxicity. These results provide evidence for a glucose-sensing pathway that negatively regulates a stress response conserved from yeast to mammalian cells. These studies also suggest that the common use of drugs that cause hyperglycemia, such as dexamethasone (Dexa) and rapamycin, could increase the toxicity of cancer drugs to normal tissues and organs while making glucose available to cancer cells.