PHLDA1 silencing in IMR-32 human neuroblastoma cells results in ABCB1 overexpression, augments chemoresistance and leads to increased growth of tumors

Abstract

Abstract PHLDA1 (pleckstrin homology-like domain, family A, member 1) is a multifunctional protein involved in pathophysiological conditions such as cancer. Our previous research revealed changes in the proteome of PHLDA1 -silenced human neuroblastoma IMR-32 cells. One of the proteins that was increased in PHLDA1 -silenced cells was the efflux pump ABCB1 (ATP binding cassette subfamily B member 1). In this study, ABCB1 efflux pump upregulation in PHLDA1 -silenced IMR-32 cells led to increased resistance of the cells to xenobiotic agents. Experiments revealed that xenograft tumors grown in immunocompromised mice from PHLDA1 -silenced cells presented multiple changes in comparison with tumors grown from control cells. Tumors grown from PHLDA1 -silenced cells were larger and contained fewer apoptotic cells than control tumors. The blood vessels within the tumors grown from PHLDA1 -silenced cells displayed increased extravasation and the extracellular matrix of the tumors presented increased collagen content in comparison to that of the control tumors. The results showed that silencing PHLDA1 in vivo promoted human neuroblastoma cell survival, decreased the apoptotic potential of the cells, disrupted angiogenesis in developing tumors, and altered collagen network formation.