Targeting PELP1 Attenuates Angiogenesis and Enhances Chemotherapy Efficiency in Colorectal Cancer

SIMPLE SUMMARY: Excessive angiogenesis is a distinct feature of colorectal cancer (CRC) and plays a pivotal role in tumor development and metastasis. Therefore, it is essential to clarify the underlying mechanism of angiogenesis. In this study, we found that the level of proline-, glutamic acid, and leucine-rich protein 1 (PELP1) was positively correlated with microvessel density (MVD). In vitro and in vivo assays further showed PELP1 regulated angiogenesis via the Signal transducer and activator of transcription 3 (STAT3)/Vascular endothelial growth factor (VEGFA). Notably, we found that inhibition of PELP1 enhanced the efficacy of chemotherapy due to vascular normalization. Thus, targeting of PELP1 may be a potentially therapeutic strategy for CRC. ABSTRACT: Abnormal angiogenesis is one of the important hallmarks of colorectal cancer as well as other solid tumors. Optimally, anti-angiogenesis therapy could restrain malignant angiogenesis to control tumor expansion. PELP1 is as a scaffolding oncogenic protein in a variety of cancer types, but its involvement in angiogenesis is unknown. In this study, PELP1 was found to be abnormally upregulated and highly coincidental with increased MVD in CRC. Further, treatment with conditioned medium (CM) from PELP1 knockdown CRC cells remarkably arrested the function of human umbilical vein endothelial cells (HUVECs) compared to those treated with CM from wildtype cells. Mechanistically, the STAT3/VEGFA axis was found to mediate PELP1-induced angiogenetic phenotypes of HUVECs. Moreover, suppression of PELP1 reduced tumor growth and angiogenesis in vivo accompanied by inactivation of STAT3/VEGFA pathway. Notably, in vivo, PELP1 suppression could enhance the efficacy of chemotherapy, which is caused by the normalization of vessels. Collectively, our findings provide a preclinical proof of concept that targeting PELP1 to decrease STAT3/VEGFA-mediated angiogenesis and improve responses to chemotherapy due to normalization of vessels. Given the newly defined contribution to angiogenesis of PELP1, targeting PELP1 may be a potentially ideal therapeutic strategy for CRC as well as other solid tumors.