Targeting the K-Ras--JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation.

Masashi Okada,Atsushi Sato,Shuhei Suzuki,Manabu Seino,Shizuka Seino,Chifumi Kitanaka,Keita Shibuya

doi:10.18632/oncotarget.2087

Abstract

Cancer cells with self-renewal and tumor-initiating capacity, either quiescent (cancer stem cells, CSCs) or proliferating (cancer stem-like cells, CSLCs), are now deemed responsible for the pervasive therapy resistance of pancreatic cancer, one of the deadliest human cancers characterized by high prevalence of K-Ras mutation. However, to date, much remains unknown how pancreatic CSCs/CSLCs are regulated. Here we show that the K-Ras - JNK axis plays a pivotal role in the maintenance of pancreatic CSCs/CSLCs. In vitro inhibition of JNK, either pharmacological or genetic, caused loss of the self-renewal and tumor-initiating capacity of pancreatic CSLCs. Importantly, JNK inhibition in vivo via systemic JNK inhibitor administration, which had no discernible effect on the general health status of mice, efficiently depleted the CSC/CSLC population within pre-established pancreatic tumor xenografts. Furthermore, knockdown of K-Ras in pancreatic CSLCs with K-Ras mutation led to downregulation of the JNK pathway as well as in loss of self-renewal and tumor-initiating capacity. Together, our findings suggest that pancreatic CSCs/CSLCs are dependent on K-Ras activation of JNK and also suggest that the K-Ras - JNK axis could be a potential target in CSC/CSLC-directed therapies against pancreatic cancer.

Highlights

Pancreatic cancer is one of the leading causes of cancer-related mortality world-wide [1, 2] and is among the deadliest of all human cancers, with a median survival less than 1 year and no more than one tenth of the patients surviving 5 years [1, 2]
Just as we observed with cancer stem-like cells (CSLCs) of glioblastoma [22], we noted during the course of our experiments that the activity of the Jun NH2-terminal kinases (JNKs) pathway, as represented by the expression of phosphorylated JNK and c-Jun, was higher in selfrenewing cells than in their differentiated counterparts (Supplementary Figure S1C)
The results indicated PANC-1 CSLCs had substantially lost their sphere-forming ability after the transient SP600125 pretreatment (Figure 1D), suggesting that JNK is required for the maintenance of the self-renewal capacity of PANC-1 CSLCs

Summary

Introduction

Pancreatic cancer is one of the leading causes of cancer-related mortality world-wide [1, 2] and is among the deadliest of all human cancers, with a median survival less than 1 year and no more than one tenth of the patients surviving 5 years [1, 2]. The pervasive resistance of pancreatic cancer against conventional chemoradiotherapy, in combination with the difficulty of early detection, is considered to be the major contributing factor to the highly dismal prognosis of this devastating disease [3,4,5]. Since the identification of cancer stem cells (CSCs) or cancer stem-like cells (CSLCs) in pancreatic cancer [6, 7], pancreatic CSCs/CSLCs have emerged as a possible, attractive explanation for the highly incorrigible therapy resistance of pancreatic cancer [8,9,10,11,12]. The molecular mechanism contributing to the maintenance of pancreatic CSCs/CSLSc have been an intense focus of recent research, with an enthusiastic expectation that elucidation of the mechanism would lead to development of effective measures to target pancreatic CSCs/ CSLCs and by so doing to substantial improvement in the prognosis of pancreatic cancer. A number of molecules and signaling pathways have been identified and implicated in the mechanism [8,9,10,11,12], much still remains to be learned as to how we can efficiently eliminate CSCs/CSLCs from tumors of pancreatic cancer, and that, in therapeutically feasible and significant manners

Methods

Results

Conclusion