In animal models, orally administered type II collagen suppressed collagen-induced arthritis as well as adjuvant arthritis - the latter presumably through secretion of anti-inflammatory cytokines by bystander T cells, or linked suppression through induction of collagen type II-specific regulatory cells and their migration to the joint [ 41- 43].
Interestingly, IRE1α activation has been recently linked to induction of autophagy through activation of the Jun-Kinase pathway [ 21].
Our data suggest that tolerogenic CD11c+ DCs are closely linked with the induction of oral tolerance through an IDO-dependent mechanism and that this pathway may provide a new therapeutic modality to treat autoimmune arthritis.
TGF-β has been linked to the induction of T-cell regulatory cells through the production of suppressor T-cells from naïve CD4+/CD25- T-cells [ 50, 85].
Antiapoptotic effects of activated Notch proteins have been linked to the induction of Bcl2 [ 26] as well as increased signaling through both the phosphatidylinositol 3-kinase (PI3 K) [ 27] and NF- κB [ 28] signaling pathways.
In line with the recent reports demonstrating the connection between loss of stemness, for example through Oct4 KD, and the resultant aberrations within autophagic homeostasis22, we found that PHGDH inhibition-related effects on self-renewal and differentiation are also linked with autophagy induction.
Other integrins have also been linked to the induction of metastasis.
Thus growth factor abrogation [ 82, 83], death induction through activation of the TNF-α receptor [ 89, 90] or genotoxic stress [ 91, 92] all are linked to the induction of massive ROS production, which is essential for cell death.
Studies in breast cancer have suggested a link to EMT through induction of Cripto-1 and the c-Src pathway [ 16], although this is contradicted by studies showing that Msx2 downregulates the prometastatic factor BSP [ 18].
Replicative senescence (RS) that limits the proliferating potential of normal eukaryotic cells occurs either by a cell-division counting mechanism linked to telomere erosion or prematurely through induction by cell stressors such as oncogene hyper-activation.
This study provides a preclinical rationale for apoptosis induction linked with the mTOR pathway through a combination of chemotherapeutic agents and mTOR inhibitor, and will support this combinatorial strategy to PC patients.
