HepaCAM inhibits the malignant behavior of castration-resistant prostate cancer cells by downregulating Notch signaling and PF-3084014 (a γ-secretase inhibitor) partly reverses the resistance of refractory prostate cancer to docetaxel and enzalutamide in vitro

Abstract

Castration-resistant prostate cancer (CRPC) continues to be a major challenge in the treatment of prostate cancer (PCa). The expression of hepatocyte cell adhesion molecule (HepaCAM), a novel tumor suppressor, is frequently downregulated or lost in PCa. Overactivated Notch signaling is involved in the development and progression of PCa, including CRPC. In this study, we found that the activities of Notch signaling were elevated, while HepaCAM expression was decreased in CRPC tissues compared with matched primary prostate cancer (PPC) tissues. In addition, HepaCAM negativity was found to be associated with a worse progression-free survival (PFS). Furthermore, the overexpression of HepaCAM induced by transfection with a HepaCAM overexpression vector (Ad-HepaCAM) exerted antitumor effects by decreasing the proliferation, and suppressing the invasion and migration of bicalutamide-resistant (Bica-R) cells and enzalutamide-resistant (Enza-R) cells. Importantly, we found that the antitumor effects of HepaCAM on the resistant cells were associated with the downregulation of Notch signaling. Moreover, we revealed that PF-3084014 (a γ-secretase inhibitor) re-sensitized Enza-R cells to enzalutamide, and sequential dual-resistant (E+D-R) cells to docetaxel. Additionally, the findings of this study demonstrated that the use of PF-3084014 alone exerted potent antitumor effect on the resistant cells in vitro. On the whole, this study indicates that HepaCAM potentially represents a therapeutic target and PF-3084014 may prove to a promising agent for use in the treatment of refractory PCa.

RETRACTED: Inhibitor 9 Combined With Androgen Deprivation Therapy or Chemotherapy Delays the Malignant Behavior of Castration-Resistant Prostate Cancer Through K-Ras/PLCε/PKCε Signaling Pathway

“…The LNCaP cell line was obtained from American type culture specimens. To induce resistance, LNCaP cells were cultured in drug resistance media (39)(40)(41). Cells exhibiting bicalutamide resistance were named R-Bica cells and LNCaP cells resistant to bicalutamide and docetaxel were named R-B+D cells as previously described (41).…”

“…The membrane was incubated overnight with the following primary antibodies: K-Ras, PLCε, and PKCε (Santa Cruz); and VEGF, MMP2, MMP9, and β-actin (Cell Signaling Technology). Next, the membrane was incubated with secondary antibody for 2 h, and finally visualized by Enhanced Chemiluminescence (41,44). Image-Pro Plus 6.0 software was used for detecting protein band intensity.…”

Inhibition of Notch pathway enhances the anti-tumor effect of docetaxel in prostate cancer stem-like cells

“…PF-03084014 is a small molecule reversible, non-competitive and selective GSI, which has been shown to inhibit Notch pathway through blocking cleaved-notch receptor formation in various types of cancer [14,[22][23][24]. Recently, a few studies have found that inhibition of Notch signaling using PF-03084014 sensitized DOX-resistant prostate cancer cells to DOX [12,25]. However, it is not completely clear that pharmacological targeting of the Notch pathway by PF-03084014 could impact DOX chemoresistance in prostate CSCs.…”

Emerging roles for multifunctional ion channel auxiliary subunits in cancer

“…GlialCAM (also called HepaCAM) was identified as a putative tumour suppressor gene that is silenced in hepatocellular carcinoma [ 278 ]. GlialCAM downregulation is observed in liver, bladder, prostate, kidney, breast, uterus, colon, stomach, and rectal cancer biopsies [ 269 , [278] , [279] , [280] , [281] , [282] ]. Functionally, when GlialCAM is expressed in the liver carcinoma cell line HepG2, cell motility and adhesion are increased, colony formation is reduced, and proliferation is reduced [ 278 ].…”