Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

Abstract

The success of chemotherapy largely depends on the anticancer immune response triggered by tumor cells that succumb to immunogenic cell death (ICD). One of the hallmarks of ICD is premortem autophagy that facilitates the release of adenosine triphosphate from dying cancer cells and acts as a chemoattractant for dendritic cell precursors. Here, we show that the immune response induced by inoculation of cancer cells undergoing ICD in response to the anthracycline mitoxantrone (MTX) can be improved by a short-term fasting regimen (48 hours of starvation) and that this effect is reversed by systemic administration of the autophagy inhibitor dimethyl α-ketoglutarate. Tumor growth reduction by MTX treatment is known to depend on autophagy induction in cancer cells as well as on an intact immune system. We compared the antitumor effects of MTX on autophagy-competent cancers implanted in wild type (WT) or partially autophagy-deficient (Becn1± or Atg4b−/-) mice. While there was no difference in the tumor growth reducing effects of MTX on tumors evolving in WT, Becn1+/- and Atg4b−/- mice, we observed an increase in the toxicity of MTX on Atg4b−/- mice. These results suggest that autophagy in cancer cells (but less so in host cells) is rate-limiting for therapeutically relevant anticancer immune responses, yet has a major role in blunting the life-threatening toxicity of chemotherapy.

α-Ketoglutarate inhibits autophagy

“…It has been claimed by several independent groups that α-ketoglutarate inhibits autophagy [21–25,33]. However, the contrary has been reported as well, namely, that α-ketoglutarate would induce autophagy [26].…”

“…Recently, several papers have been published that claim contradictory effects of α-ketoglutarate on autophagy. Several works indicate that addition of the α-ketoglutarate precursor dimethyl α-ketoglutarate (DMKG) to human cell cultures or its intraperitoneal injection into mice effectively inhibits autophagy through an anaplerosis-dependent increase in acetyl-CoA (AcCoA) levels, thus, increasing the acetylation of cytoplasmic proteins [21–25]. In contrast, another paper claims that addition of another α-ketoglutarate precursor, octyl α-ketoglutarate (O-KG) induces autophagy both in human cells and in Caenorhabditis elegans , because it inhibits the mitochondrial ATP synthase as well as MTORC1 [26,27].…”

Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

“…Up till now, contradictory effects of αKG on autophagy have been reported. Several studies demonstrate that addition of the αKG to mammalian cells or its administration into mice effectively inhibits autophagy [41][42][43][44] . In sharp contrast, Chin et al have shown that αKG inhibits mTORC1 and the mitochondrial ATP synthase and therefore induces autophagy both in mammalian cells and in Caenorhabditis elegans 26,45 .…”

A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice

“…[16][17][18][19] ICD inducers are widely used in cancer therapy and are still undergoing clinical evaluation. 20,21 One of the premortem responses that is elicited by ICDinducing chemotherapeutics is autophagy, 22 which in turn facilitates the release of adenosine triphosphate (ATP) from dying cancer cells. 23 Extracellular ATP acts on purinergic receptors to attract DC precursors into the tumor bed and to facilitate their local activation.…”