NPC-26 kills human colorectal cancer cells via activating AMPK signaling.

Zhen Zhao,Deshan Cheng,Keyu Sun,Weiping Xu,Li Feng,Mei Liu,Jiqin Wang,Meirong Ling

doi:10.18632/oncotarget.15436

Abstract

NPC-26 is novel mitochondrion-interfering compound. The current study tested its potential effect against colorectal cancer (CRC) cells. We demonstrated that NPC-26 induced potent anti-proliferative and cytotoxic activities against CRC cell lines (HCT-116, DLD-1 and HT-29). Activation of AMP-activated protein kinase (AMPK) signaling mediated NPC-26-induced CRC cell death. AMPKα1 shRNA knockdown or dominant negative mutation abolished NPC-26-induced AMPK activation and subsequent CRC cell death. NPC-26 disrupted mitochondrial function, causing mitochondrial permeability transition pore (mPTP) opening and reactive oxygen species (ROS) production. ROS scavengers (NAC or MnTBAP) and mPTP blockers (cyclosporin A or sanglifehrin A) blocked NPC-26-induced AMPK activation and attenuated CRC cell death. Significantly, intraperitoneal injection of NPC-26 potently inhibited HCT-116 tumor growth in severe combined immuno-deficient (SCID) mice. Yet, its anti-tumor activity was significantly weakened against AMPKα1-silenced HCT-116 tumors. Together, we conclude that NPC-26 kills CRC cells possibly via activating AMPK signaling.

Highlights

Colorectal cancer (CRC) is still a major malignancy in the world, which causes significant mortality each year [1,2,3]
Above inhibitors alleviated NPC-26-induced killing of HCT-116 cells (Figure 4D and 4E). Treatment with these inhibitors alone didn’t affect AMPK activation and HCT-116 cell survival/ death (Data not shown). These results suggest that NPC-26 induces mitochondrial dysfunction, which possibly leads to AMPK activation and subsequent cell death
When analyzing tumor tissue samples, we found that NPC-26 administration (12 hours after initial administration) induced significant AMPK activation, or p-AMPK/p-ACC, in control tumors (Figure 5B, left panel), which was absent in tumors expressing AMPKα1 short hairpin RNA (shRNA) (Figure 5B, left panel)

Summary

Introduction

Colorectal cancer (CRC) is still a major malignancy in the world, which causes significant mortality each year [1,2,3]. Recent studies have developed a small-molecule mitochondrion-interfering compound, named NPC-26 [6]). It disturbs normal mitochondrial functions, causing mitochondrial permeability transition pore (mPTP) opening and reactive oxygen species (ROS) production, and eventually leading to cell death [6, 7]. NPC-26 induces a conversion from elongated to punctate mitochondria, and provokes non-apoptotic cell death which is BAX-/BAK-independent [6]. Further studies have proposed that NPC26-induced cell death is dependent on activation of kinase signaling pathways [6]. The underlying signaling mechanisms of NPC-26-induced cell death are still vague. We suggest that NPC-26 kills human CRC cells possibly via activating AMP-activated protein kinase (AMPK) signaling

Methods

Results

Conclusion