Krüppel-like factor 4 mediates lysophosphatidic acid-stimulated migration and proliferation of PC3M prostate cancer cells

Abstract

Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer mortality among men in the United States. Accumulating evidence suggests that lysophosphatidic acid (LPA) serves as an autocrine/paracrine mediator to affect initiation, progression and metastasis of prostate cancer. In the current study, we demonstrate that LPA stimulates migration and proliferation of highly metastatic human prostate cancer, PC-3M-luc-C6 cells. LPA-induced migration of PC-3M-luc-C6 cells was abrogated by pretreatment of PC-3M-luc-C6 cells with the LPA receptor 1/3 inhibitor Ki16425 or small interfering RNA (siRNA)-mediated silencing of endogenous LPA receptor 1, implicating a key role of the LPA-LPA receptor 1 signaling axis in migration of PC-3M-luc-C6 cells. In addition, LPA treatment resulted in augmented expression levels of Krüppel-like factor 4 (KLF4), and siRNA or short-hairpin RNA (shRNA)-mediated silencing of KLF4 expression resulted in the abolishment of LPA-stimulated migration and proliferation of PC-3M-luc-C6 cells. shRNA-mediated silencing of KLF4 expression resulted in the inhibition of in vivo growth of PC-3M-luc-C6 cells in a xenograft transplantation animal model. Taken together, these results suggest a key role of LPA-induced KLF4 expression in cell migration and proliferation of prostate cancer cells in vitro and in vivo. Researchers in South Korea have identified key factors in the migration and proliferation of human prostate cancer cells. Cell movement is a critical step in the progression of prostate cancer, a major cause of cancer deaths in men. The team led by Jae Ho Kim of Pusan National University found that lysophosphatidic acid (LPA), a component of cell signalling systems, stimulates the migration and proliferation of highly invasive cells derived from human prostate cancer tissue. They demonstrated that this process is mediated by Krüppel-like Factor 4, a protein that regulates gene activity by binding to DNA. They also showed that LPA's effects depend on it binding to a specific LPA-receptor protein on cell membranes. This research offers potential new targets and mechanisms for developing drugs to fight prostate cancer.