Receptor interactive protein kinase 3 promotes Cisplatin-triggered necrosis in apoptosis-resistant esophageal squamous cell carcinoma cells

Yang Xu; Zhengwei Lin; Nan Zhao; Lanping Zhou; Fang Liu; Zbigniew Cichacz; Lin Zhang; Qimin Zhan; Xiaohang Zhao

doi:10.1371/journal.pone.0100127

Receptor interactive protein kinase 3 promotes Cisplatin-triggered necrosis in apoptosis-resistant esophageal squamous cell carcinoma cells

PLoS One. 2014 Jun 24;9(6):e100127. doi: 10.1371/journal.pone.0100127. eCollection 2014.

Authors

Yang Xu¹, Zhengwei Lin¹, Nan Zhao¹, Lanping Zhou¹, Fang Liu¹, Zbigniew Cichacz², Lin Zhang³, Qimin Zhan¹, Xiaohang Zhao⁴

Affiliations

¹ State Key Laboratory of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
² Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America.
³ Departments of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
⁴ State Key Laboratory of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Center of Basic Medical Sciences, Navy General Hospital, Beijing, China.

Abstract

Cisplatin-based chemotherapy is currently the standard treatment for locally advanced esophageal cancer. Cisplatin has been shown to induce both apoptosis and necrosis in cancer cells, but the mechanism by which programmed necrosis is induced remains unknown. In this study, we provide evidence that cisplatin induces necrotic cell death in apoptosis-resistant esophageal cancer cells. This cell death is dependent on RIPK3 and on necrosome formation via autocrine production of TNFα. More importantly, we demonstrate that RIPK3 is necessary for cisplatin-induced killing of esophageal cancer cells because inhibition of RIPK1 activity by necrostatin or knockdown of RIPK3 significantly attenuates necrosis and leads to cisplatin resistance. Moreover, microarray analysis confirmed an anti-apoptotic molecular expression pattern in esophageal cancer cells in response to cisplatin. Taken together, our data indicate that RIPK3 and autocrine production of TNFα contribute to cisplatin sensitivity by initiating necrosis when the apoptotic pathway is suppressed or absent in esophageal cancer cells. These data provide new insight into the molecular mechanisms underlying cisplatin-induced necrosis and suggest that RIPK3 is a potential marker for predicting cisplatin sensitivity in apoptosis-resistant and advanced esophageal cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Apoptosis / genetics*
Apoptosis Regulatory Proteins
Carcinoma, Squamous Cell / genetics*
Carcinoma, Squamous Cell / metabolism
Carcinoma, Squamous Cell / pathology*
Cell Line, Tumor
Cisplatin / pharmacology*
Disease Models, Animal
Esophageal Neoplasms / genetics*
Esophageal Neoplasms / metabolism
Esophageal Neoplasms / pathology*
Esophageal Squamous Cell Carcinoma
Gene Expression Regulation, Neoplastic / drug effects
Gene Knockout Techniques
Humans
Intracellular Signaling Peptides and Proteins / deficiency
Mice
Mitochondrial Proteins / deficiency
Necrosis / chemically induced
Necrosis / genetics*
RNA Interference
Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
Signal Transduction
Tumor Burden / drug effects
Tumor Burden / genetics
Tumor Necrosis Factor-alpha / biosynthesis
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Apoptosis Regulatory Proteins
DIABLO protein, human
Intracellular Signaling Peptides and Proteins
Mitochondrial Proteins
Tumor Necrosis Factor-alpha
RIPK1 protein, human
RIPK3 protein, human
Receptor-Interacting Protein Serine-Threonine Kinases
Cisplatin

Grants and funding

This work was supported by grants from the NSFC (No. 81071811, 91029725, 81321091, 81372591, 81372385), the National High-tech R & D Program (No. 2012AA020206, 2012AA02A503), and the State Key Projects for Basic Research (No. 2011CB910703) of China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.