Mitochondrial oncobioenergetic index: A potential biomarker to predict progression from indolent to aggressive prostate cancer.

Praveen K Vayalil,Aimee Landar

doi:10.18632/oncotarget.5487

Praveen K Vayalil, Aimee Landar

Open Access

https://doi.org/10.18632/oncotarget.5487

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Journal: Oncotarget	Publication Date: Oct 15, 2015
Citations: 24	License type: cc-by

Affiliation: University of Alabama at Birmingham

Abstract

Mitochondrial function is influenced by alterations in oncogenes and tumor suppressor genes and changes in the microenvironment occurring during tumorigenesis. Therefore, we hypothesized that mitochondrial function will be stably and dynamically altered at each stage of the prostate tumor development. We tested this hypothesis in RWPE-1 cells and its tumorigenic clones with progressive malignant characteristics (RWPE-1 < WPE-NA22 < WPE-NB14 < WPE-NB11 < WPE-NB26) using high-throughput respirometry. Our studies demonstrate that mitochondrial content do not change with increasing malignancy. In premalignant cells (WPE-NA22 and WPE-NB14), OXPHOS is elevated in presence of glucose or glutamine alone or in combination compared to RWPE-1 cells and decreases with increasing malignancy. Glutamine maintained higher OXPHOS than glucose and suggests that it may be an important substrate for the growth and proliferation of prostate epithelial cells. Glycolysis significantly increases with malignancy and follow a classical Warburg phenomenon. Fatty acid oxidation (FAO) is significantly lower in tumorigenic clones and invasive WPE-NB26 does not utilize FAO at all. In this paper, we introduce for the first time the mitochondrial oncobioenergetic index (MOBI), a mathematical representation of oncobioenergetic profile of a cancer cell, which increases significantly upon transformation into localized premalignant form and rapidly falls below the normal as they become aggressive in prostate tumorigenesis. We have validated this in five prostate cancer cell lines and MOBI appears to be not related to androgen dependence or mitochondrial content, but rather dependent on the stage of the cancer. Altogether, we propose that MOBI could be a potential biomarker to distinguish aggressive cancer from that of indolent disease.

Highlights

Prostate cancer is a major cause of cancer-related mortality and morbidity in males especially in older men (60–70 years) worldwide [1]
This indicates that mitochondrial content of these cells does not change with tumorigenic transformation and any potential differences in oncobioenergetic parameters among these cells would not be influenced by the cellular mitochondrial content
Regardless of the specific mechanism by which they contribute to mitochondrial dysfunction, the oncobioenergetic functional signature of epithelial cells during the step-wise progression from normal to aggressive cancer has not been explored in prostate cancer

Summary

Introduction

Prostate cancer is a major cause of cancer-related mortality and morbidity in males especially in older men (60–70 years) worldwide [1]. Among American men, prostate cancer is the second leading cause of cancer death. A significant fraction of prostate cancers detected solely on the basis of an increased serum PSA are subclinical indolent tumors, while only a small fraction of these tumors progress into an aggressive form, providing a major clinical challenge to distinguish between the two. The future progress in combating prostate cancer will be highly dependent upon the availability of improved diagnostic tools to distinguish aggressive forms of cancer from indolent tumor early enough to deliver appropriate treatment strategies to achieve a disease-free state and to reduce over-diagnosis and overtreatment [4, 5]

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