Targeting the MIF/CXCR7/AKT Signaling Pathway in Castration-Resistant Prostate Cancer

Abstract

Although androgen deprivation therapy (ADT) is an effective treatment for metastatic prostate cancer, incurable castration-resistant prostate cancer (CRPC) inevitably develops. Importantly, androgen receptor (AR) continues to be critical for prostate cancer growth and progression after ADT. One of the underlying molecular mechanisms is derepression of AR-repressed genes involved in cell cycle and proliferation after ADT. Here, the data demonstrate that C-X-C chemokine receptor type 7 (CXCR7), a seven-transmembrane G-protein-coupled chemokine receptor, is an AR-repressed gene and is upregulated after ADT. AR directly regulates CXCR7 using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) gene editing. Macrophage migration inhibitory factor (MIF) was identified as a ligand for CXCR7, which induces expression of cell-cycle genes through activating AKT signaling pathway. Previous studies have been focused on chemokine CXCL12 and its receptor CXCR4 in mediating metastasis of various cancer types, including prostate cancer. The critical roles of CXCL12/CXCR4 axis in the interaction between cancer cells and their microenvironment render it a promising therapeutic target in cancer treatment. The data suggest that the MIF/CXCR7/AKT pathway drives CRPC growth and metastasis independent of the CXCL12/CXCR4 axis. Furthermore, CXCR7 blockade in combination with anti-androgen enzalutamide inhibits CRPC tumor growth and potentially prevents metastasis. Notably, both MIF and CXCR7 are overexpressed in CRPC patient specimens and therefore are attractive therapeutic targets for these patients. This work suggests that CXCR7 plays more important roles than CXCR4 in CRPC progression; thus, targeting CXCR7 in combination with anti-androgen is a promising therapeutic approach for metastatic CRPC.

RUNX2 overexpression and PTEN haploinsufficiency cooperate to promote CXCR7 expression and cellular trafficking, AKT hyperactivation and prostate tumorigenesis

“…This data is consistent with the finding that Runx2 protein level was lower in HGPIN of Cre + ; Pten p/p mice compared to double mutant mice (Figure S1A, right), further supporting the importance of the Runx2 protein level in regulation of Cxcr7 expression in PTEN-deficient background. Two groups have shown most recently that CXCR7 is a repression target of AR and increased expression of CXCR7 contributes to castration resistance in prostate cancer 33, 34. The expression of AR protein was comparable in the prostate of the four groups of mice we studied (Figure S6C), suggesting that increased expression of CXCR7 in the cell membrane in the prostate tumors of Runx2 transgenic- Pten +/- mice was less likely mediated by AR function.…”

PRMT6 Promotes Lung Tumor Progression via the Alternate Activation of Tumor-Associated Macrophages

“…Of note, these cytokines were not previously associated with either ILF2 or PRMT6. Macrophage MIF was of interest due to its protumorigenic role in a number of cancer types (38)(39)(40)(41), and due to its most prominent induction by ILF2 (Fig. 6B).…”

Mechanisms of enzalutamide resistance in castration‐resistant prostate cancer and therapeutic strategies to overcome it

“…xenografts (PDX) models of castration-resistant prostate cancer (Li, Fong, et al, 2019;Luo et al, 2018;Rafiei et al, 2019). Similarly, other cytokines, such as FGF, GM-CSF and IL-10, were found to be elevated in the circulation of metastic castration-resistant prostate cancer patients resistant to enzalutamide (Pal et al, 2019).…”

“…It was reported that CXCR7 could interact with the epidermal growth receptor (EGFR) and stimulate increased levels of phospho‐EGFR (p‐EGFR). The effect of the combination of CXCR7 inhibitors and enzalutamide was manifested by significant growth inhibition of prostate cancer cell line xenografts and patient‐derived xenografts (PDX) models of castration‐resistant prostate cancer (Li, Fong, et al, 2019; Luo et al, 2018; Rafiei et al, 2019). Similarly, other cytokines, such as FGF, GM‐CSF and IL‐10, were found to be elevated in the circulation of metastic castration‐resistant prostate cancer patients resistant to enzalutamide (Pal et al, 2019).…”