Upon activation by stromal cell derived factor 1 alpha (SDF1 alpha), the G-protein-coupled chemokine receptor, CXCR4, generates signals that eventually lead to the metastatic spread and survival of primary tumor cells in distal organs. Indeed, elevated expression of CXCR4 protein in prostate tissues correlates with metastasis and overall prediction of poor survival. CXCR4 can form homodimers or can heterodimerize with unrelated receptors, such as the delta opioid receptor (DOR). Simultaneous treatment with appropriate agonists for the individual receptors that are heterodimerizing, such as the CXCR4/DOR heterodimer, results in a dimer that is unable to signal, although each receptor can bind its respective ligand. Therefore, heterodimerization can cause decreased signaling through such receptor complexes, representing functional desensitization. In the context of cancer treatment, CXCR4 signaling and subsequent functions can be silenced by desensitization through heterodimeric association with other receptors, thereby inhibiting CXCR4-generated signals that would otherwise lead to metastasis. Thus, antagonizing the function of CXCR4 through heterodimerization could be a rational approach to the prevention and management of metastatic prostate cancer, and could be an effective alternative to current therapeutics involving neutralizing antibodies or antagonists against CXCR4, both of which have undesirable consequences. Studies reported that simultaneous treatment with CXCR4 and cannabinoid receptor 2 (CB2R) agonists caused a reduction in CB2R-induced analgesia, suggesting a functional desensitization of CB2R, although dimerization was not analyzed. Given this scenario, a heterodimer of CXCR4/CB2R could potentially attenuate responses triggered individually by CXCR4 or CB2R, without the side effects experienced with the use of receptor antibodies or antagonists, especially in situations where both receptors are expressed on the same tumor cells. We will demonstrate that receptor heterodimerization could form the molecular basis for decreasing CXCR4-mediated signaling, and therefore, metastasis. Hypothesis: CXCR4 function can be abrogated by simultaneous ligand-dependent heterodimerization of CXCR4 with CB2R, resulting in decreased CXCR4 signaling, cell metastasis and overall tumor development.
Specific aims : (1): To determine whether CXCR4 and CB2R physically associate in vitro;(2): To determine which signaling pathways are modulated as a result of heterodimerization of CXCR4 with CB2R;and (3): To determine whether heterodimerization of CXCR4 with CB2R antagonizes CXCR4-mediated metastasis in intact animals. Research design: Our strategy will include: (i) confirming that CXCR4 and CB2R dimerize by FRET analysis;(ii) determining whether CB2R is required as a dimer partner to abrogate signaling and known functions of CXCR4 by shRNA for CB2R;and (iii) examining whether heterodimerization of CXCR4 with CB2R will inhibit tumor growth and metastasis of prostate cancer cells to the bone in vivo.
Receptor heterodimerization could naturally control cancer signals triggered individually by CXCR4, without the side effects of current therapeutics, especially in situations where the heterodimerizing receptors are expressed on the same tumor cell. Moreover, stabilization of the CXCR4/CB2R receptor dimer could represent a natural mechanism that alerts the organism to tumor formation, by reducing the signaling potential of CXCR4, and subsequently, the metastatic potential of prostate cancer cells.
|Coke, Christopher J; Scarlett, Kisha A; Chetram, Mahandranauth A et al. (2016) Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveals a Mechanism for Regulation of Tumor Progression. J Biol Chem 291:9991-10005|