Apoptosis-induced nuclear expulsion in tumor cells drives S100a4-mediated metastatic outgrowth through the RAGE pathway

Abstract

Most tumor cells undergo apoptosis in circulation and at the metastatic organ sites due to host immune surveillance and a hostile microenvironment. It remains to be elucidated whether dying tumor cells have a direct effect on live tumor cells during the metastatic process and what the underlying mechanisms are. Here we report that apoptotic cancer cells enhance the metastatic outgrowth of surviving cells through Padi4-mediated nuclear expulsion. Tumor cell nuclear expulsion results in an extracellular DNA–protein complex that is enriched with receptor for advanced glycation endproducts (RAGE) ligands. The chromatin-bound RAGE ligand S100a4 activates RAGE receptors in neighboring surviving tumor cells, leading to Erk activation. In addition, we identified nuclear expulsion products in human patients with breast, bladder and lung cancer and a nuclear expulsion signature correlated with poor prognosis. Collectively, our study demonstrates how apoptotic cell death can enhance the metastatic outgrowth of neighboring live tumor cells.

Antiproliferative and Apoptotic Effects of Tempol, Methotrexate, and Their Combinations on the MCF7 Breast Cancer Cell Line

“…Bax also counteracts the apoptosis-suppressing activity of Bcl-2. 19 Apart from these proteins, apoptosis is regulated by the balance between pro-apoptotic proteins such as Bad, Bak, Bclxs, and pro-caspases and antiapoptotic proteins such as Bcl-xl and Bcl-w. 6 Caspase-3, also recognized as the "executioner caspase", is triggered by initiator caspases such as caspase-8, caspase-9, or caspase-10. It holds a crucial role in the apoptotic pathway by aiding in the breakdown of various proteins within the cell, among which is poly(ADP-ribose) polymerase.…”

“…It holds a crucial role in the apoptotic pathway by aiding in the breakdown of various proteins within the cell, among which is poly(ADP-ribose) polymerase. 5,6 It was reported that increasing doses of TPL administration induced apoptosis by significantly increasing caspase-3 activation in As4.1 juxtaglomerular cells. 21 The apoptotic effects of TPL on cancer cells may also occur by inducing oxidative stress in cells.…”

“…7 The development of resistance to apoptosis causes tumor formation by reducing the loss of damaged cells. 6 This situation leads to inadequacy of chemotherapeutic drugs used in the treatment of cancer. For this reason, treatments that target the destruction of tumor cells while having few side effects on healthy cells are being investigated.…”

“…Chemotherapeutic agents used in the treatment cause significant damage to cell deoxyribonucleic acid (DNA) by affecting healthy cells as well as cancer cells . Since the mutations in cell DNA can cause cancer formation, destroying these cells through apoptosis is important …”

“…Apoptosis is the controlled death of senescent, harmful, or damaged cells . The development of resistance to apoptosis causes tumor formation by reducing the loss of damaged cells . This situation leads to inadequacy of chemotherapeutic drugs used in the treatment of cancer.…”