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Cancer Res. 2016 Nov 1;76(21):6351-6361. Epub 2016 Sep 2.

Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1.

Author information

1
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
2
Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
3
Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, Maryland.
4
Department of Pathology, Seirei Mikatahara Hospital, Hamamatsu, Japan.
5
Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
6
Department of Cell and Developmental Biology, Weill Medical College, Cornell University, New York, New York.
7
Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.
8
Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
9
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. tlw@jhmi.edu.

Abstract

The evolution of chemoresistance is a fundamental characteristic of cancer that ultimately hampers its clinical management. However, it may be possible to improve patient outcomes significantly by a better understanding of resistance mechanisms, which cancers rely upon during the evolution to an untreatable state. Here we report an essential role of the stem cell reprogramming factor, PBX1, in mediating chemoresistance in ovarian carcinomas. In the clinical setting, high levels of PBX1 expression correlated with shorter survival in post-chemotherapy ovarian cancer patients. In tumor cells with low endogenous levels of PBX1, its enforced expression promoted cancer stem cell-like phenotypes, including most notably an increase in resistance to platinum-based therapy used most commonly for treating this disease. Conversely, silencing PBX1 in platinum-resistant cells that overexpressed PBX1 sensitized them to platinum treatment and reduced their stem-like properties. An analysis of published genome-wide chromatin immunoprecipitation data indicated that PBX1 binds directly to promoters of genes involved in stem cell maintenance and the response to tissue injury. We confirmed direct regulation of one of these genes, STAT3, demonstrating that the PBX1 binding motif at its promoter acted to positively regulate STAT3 transcription. We further demonstrated that a STAT3/JAK2 inhibitor could potently sensitize platinum-resistant cells to carboplatin and suppress their growth in vivo Our findings offer a mechanistic rationale to target the PBX1/STAT3 axis to antagonize a key mechanism of chemoresistance in ovarian cancers and possibly other human cancers. Cancer Res; 76(21); 6351-61.

PMID:
27590741
DOI:
10.1158/0008-5472.CAN-16-0980
[Indexed for MEDLINE]
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