1. Academic Validation
  2. Adipocyte-driven unfolded protein response is a shared transcriptomic signature of metastatic prostate carcinoma cells

Adipocyte-driven unfolded protein response is a shared transcriptomic signature of metastatic prostate carcinoma cells

  • Biochim Biophys Acta Mol Cell Res. 2021 Oct;1868(11):119101. doi: 10.1016/j.bbamcr.2021.119101.
Mackenzie K Herroon 1 Shane Mecca 1 Alex Haimbaugh 2 Laimar C Garmo 1 Erandi Rajagurubandara 1 Sokol V Todi 3 Tracie R Baker 2 Izabela Podgorski 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United States of America.
  • 2 Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United States of America; Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, United States of America.
  • 3 Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United States of America; Department of Neurology, Wayne State University School of Medicine, Detroit, MI, United States of America.
  • 4 Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United States of America; Department of Oncology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, MI, United States of America. Electronic address: ipodgors@med.wayne.edu.
Abstract

A critical unknown in the field of skeletal metastases is how Cancer cells find a way to thrive under harsh conditions, as exemplified by metastatic colonization of adipocyte-rich bone marrow by prostate carcinoma cells. To begin understanding molecular processes that enable tumor cells to survive and progress in difficult microenvironments such as bone, we performed unbiased examination of the transcriptome of two different prostate Cancer cell lines in the absence or presence of bone marrow adipocytes. Our RNAseq analyses and subsequent quantitative PCR and protein-based assays reveal that upregulation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) genes is a shared signature between metastatic prostate carcinoma cell lines of different origin. Pathway analyses and pharmacological examinations highlight the ER chaperone BIP as an upstream coordinator of this transcriptomic signature. Additional patient-based data support our overall conclusion that ER stress and UPR induction are shared, important factors in the response and adaptation of metastatic tumor cells to their micro-environment. Our studies pave the way for additional mechanistic investigations and offer new clues towards effective therapeutic interventions in metastatic disease.

Keywords

BIP; Bone marrow adipocyte; Bone metastasis; ER stress; HSPA5; Prostate cancer; Unfolded protein response.

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