Abstract
Cancer associated fibroblasts (CAFs) are key determinants of cancer progression. In prostate carcinoma (PCa), CAFs induce epithelial-mesenchymal transition (EMT) and metabolic reprogramming of PCa cells towards oxidative phosphorylation (OXPHOS), promoting tumor growth and metastatic dissemination. We herein establish a novel role for pyruvate kinase M2 (PKM2), an established effector of Warburg-like glycolytic behavior, in OXPHOS metabolism induced by CAFs. Indeed, CAFs promote PKM2 post-translational modifications, such as cysteine oxidation and Src-dependent tyrosine phosphorylation, allowing nuclear migration of PKM2 and the formation of a trimeric complex with hypoxia inducible factor-1α (HIF-1α) and the transcriptional repressor Differentially Expressed in Chondrocytes-1 (DEC1). DEC1 recruitment is mandatory for downregulating miR205 expression, thereby fostering EMT execution and metabolic switch toward OXPHOS. Furthermore, the analysis of a cohort of PCa patients reveals a significant positive correlation between PKM2 nuclear localization and cancer aggressiveness, thereby validating our in vitro observations. Crucially, in vitro and in vivo pharmacological targeting of PKM2 nuclear translocation using DASA-58, as well as metformin, impairs metastatic dissemination of PCa cells in SCID mice. Our study indicates that impairing the metabolic tumor:stroma interplay by targeting the PKM2/OXPHOS axis, may be a valuable novel therapeutic approach in aggressive prostate carcinoma.
Highlights
The acquisition of malignant traits of a cell during tumorigenesis is strongly influenced by the surrounding microenvironment [1, 2]
We show that 24 h administration of Cancer associated fibroblasts (CAFs) conditioned medium (CM) to PC3 cells leads to transient oxidation of pyruvate kinase M2 (PKM2), which reverts to the reduced state after 48 h of CAFs conditioning (Figure 1A)
A similar result was obtained by treating PC3 cells with human prostate fibroblasts (HPFs) activated in vitro by exposure to CM derived from prostate carcinoma (PCa) cells (PCaAF) (Figure 1A)
Summary
The acquisition of malignant traits of a cell during tumorigenesis is strongly influenced by the surrounding microenvironment [1, 2]. Among stromal cells, cancerassociated fibroblasts (CAFs) cross-talk with cancer cells to sustain tumor growth and enhance metastatic potential [3,4,5]. This bidirectional interplay has been reported in melanoma [6], breast [7] and prostate cancers (PCa) [8]. (MMP-2 and -9), eliciting a redox-dependent epithelial-tomesenchymal transition (EMT) in PCa cells. This results in the enhancement of invasive abilities, acquisition of stem-like traits leading to metastatic dissemination [8, 9]. PCa cells decrease miR205 expression upon CAFs contact, allowing de-repression of ZEB1/2 transcription factors and promoting EMT [11]
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