The anti-tumour effects of a low protein diet and IRE1a signaling
Nutritional interventions are investigated in the context of non-communicable diseases such as cancer. Dietary regimens such as caloric restriction, fasting, ketogenic and protein-restricted diets have shown benefits to control tumor progression. Indeed, we have previously reported the protective effect of an isocaloric diet partially reduced in protein in several cancer mouse models. Beyond a stronger anticancer immunosurveillance dependent on cytotoxic T cells, the low protein diet limited tumor growth in an IRE1α-dependent manner.
Inositol-requiring enzyme 1α (IRE1α) is the most evolutionally conserved ER (endoplasmic reticulum) stress sensor induced as part of the Unfolded Protein Response (UPR). The UPR is activated by accumulation of misfolded proteins in the ER, lipidic disturbances in the ER membrane, hypoxia and nutrient deprivation. IRE1α activates downstream targets via its endoribonuclease activity resulting in XBP1 splicing as well as degradation of RNAsby a process known as the Regulated IRE1-Dependent Decay (RIDD). While XBP1 splicing recovers cellular homeostasis, massive RIDD induction leads to apoptosis under chronic ER stress.
The IRE1α signaling has been described to play dual roles in most hallmarks of cancer. While the IRE1α-XBP1 axis in tumor cells supports tumor progression in several solid and liquid oncogenic malignancies, the IRE1α-RIDD branch has been suggested as tumor-suppressive in glioblastoma. Since our previous findings showed that IRE1a is implicated in the tumor-protective effects of a low protein diet, we investigated the effect of the exogenous expression of IRE1a in tumor cells implanted in immunocompetent mice.
We found that overexpression of IRE1a and self-induction of its full RNAse activity was detrimental for subcutaneous tumor growth of colorectal and Lewis lung carcinomas. Tumors with higher IRE1a activity were characterized by active IRE1α-XBP1 and IRE1α-RIDD branches, a higher anticancer immunosurveillance and tumor cells undergoing apoptosis. The enhanced anti-cancer immune response elicits upon IRE1α overexpression was mainly dependent on T cell-mediated-cytotoxicity. In conclusion, our findings support the notion that IRE1α with a full RNAse activity can have tumor-suppressive roles.
Cancer, diet, ER stress, anti-cancer immune response, IRE1α, apoptosis
Dr. Frédéric BOST, C3M, Université Côte d’Azur
Dr. Massimiliano MAZZONE, VIB-KU Leuven Center for Cancer Biology
Dr. Serge MANIÉ, CNRS 5286, Cancer Research of Lyon
PhD supervisor :
Dr. Jean-Ehrland RICCI, C3M, Université Côte d’Azur