Mitochondrial ROS1 Increases Mitochondrial Fission and Respiration in Oral Squamous Cancer Carcinoma.

Yu-Jung Chang,Linyi Chen,Kuan-Wei Chen

doi:10.3390/cancers12102845

Abstract

Simple SummaryThe clinical efficacy of anti-epidermal growth factor receptor (EGFR) antibody cetuximab for oral squamous cell carcinomas (OSCCs) is low. We previously reported that an increased oncogenic ROS proto-oncogene 1 (ROS1) is responsible for the invasiveness and metastasis of OSCC. This study demonstrates for the first time that ROS1, a receptor tyrosine kinase, can localize to mitochondria. Mitochondrial ROS1 in the highly invasive OSCC promotes mitochondrial fission, enhances mitochondrial oxidative phosphorylation and ATP production but reduces mitochondrial biogenesis. These findings highlight the novel function of ROS1 in mitochondrial morphogenesis and metabolic adaptation to promote OSCC invasiveness.Increased ROS proto-oncogene 1 (ROS1) expression has been implicated in the invasiveness of human oral squamous cell carcinoma (OSCC). The cellular distribution of ROS1 has long-been assumed at the plasma membrane. However, a previous work reported a differential cellular distribution of mutant ROS1 derived from chromosomal translocation, resulting in increased carcinogenesis. We thus hypothesized that cellular distribution of upregulated ROS1 in OSCC may correlate with invasiveness. We found that ROS1 can localize to mitochondria in the highly invasive OSCC and identified a mitochondria-targeting signal sequence in ROS1. We also demonstrated that ROS1 targeting to mitochondria is required for mitochondrial fission phenotype in the highly invasive OSCC cells. OSCC cells expressing high levels of ROS1 consumed more oxygen and had increased levels of cellular ATP levels. Our results also revealed that ROS1 regulates mitochondrial biogenesis and cellular metabolic plasticity. Together, these findings demonstrate that ROS1 targeting to mitochondria enhances OSCC invasion through regulating mitochondrial morphogenesis and cellular respiratory.

Highlights

Oral cancer is the sixth-most-common cancer worldwide, and approximately 90% of oral cancers are oral squamous cell carcinomas (OSCCs)
The fact that significant parts of ROS proto-oncogene 1 (ROS1) localized to mitochondria (Figure 1) and cancer metastasis was linked to dysregulated mitochondrial morphogenesis [15,16], we investigated whether mitochondrial ROS1 could enhance OSCC
Inhibition of ROS1 activity results in reduced cell proliferation, migration, and invasion of OSCC cells [7], so we investigated whether suppression of ROS1 activity could block mitochondrial fission

Summary

Introduction

Oral cancer is the sixth-most-common cancer worldwide, and approximately 90% of oral cancers are oral squamous cell carcinomas (OSCCs). Most patients with oral cancer are diagnosed at an advanced stage with neck lymph-node metastasis [1]. The monoclonal antibody therapeutic cetuximab, which targets epidermal growth factor receptor (EGFR), is the most commonly prescribed treatment for advanced OSCC [2], its clinical efficacy is limited [3,4] owing to drug resistance or lack of response [5]. OSCC metastasis is essential for designing more effective therapeutic approaches. Receptor tyrosine kinases (RTKs) are synthesized in the endoplasmic reticulum, delivered to the Golgi, and targeted to the plasma membrane as single-transmembrane proteins where they transduce extracellular signals to orchestrate diverse physiological responses [6].

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Conclusion