6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-2 regulates TP53-dependent paclitaxel sensitivity in ovarian and breast cancers

Hailing Yang, Zhang Shu, Yongying Jiang, Weiqun Mao, Lan Pang, Abena Redwood, Sabrina L. Jeter-Jones, Nicholas B. Jennings, Argentina Ornelas, Jinhua Zhou, Cristian Rodriguez-Aguayo, Geoffrey Bartholomeusz, La Kesla R. Iles, Niki M. Zacharias Millward, Steven Millward, Gabriel Lopez, Xiao Feng Le, Ahmed A. Ahmed, Helen Piwnica-Worms, Anil K Sood & 2 others Robert C Bast Jr, Zhen Lu

Research output: Contribution to journalArticle

Abstract

Purpose: Paclitaxel is an integral component of primary therapy for breast and epithelial ovarian cancers, but less than half of these cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases. Experimental Design: Twelve kinases that regulate metabolism were depleted in multiple ovarian and breast cancer cell lines to determine whether they regulate sensitivity to paclitaxel in Sulforhodamine B assays. The effects of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2) depletion on cell metabolomics, extracellular acidification rate, nicotinamide adenine dinucleotide phosphate, reactive oxygen species (ROS), and apoptosis were studied in multiple ovarian and breast cancer cell lines. Four breast and ovarian human xenografts and a breast cancer patient-derived xenograft (PDX) were used to examine the knockdown effect of PFKFB2 on tumor cell growth in vivo. Results: Knockdown of PFKFB2 inhibited clonogenic growth and enhanced paclitaxel sensitivity in ovarian and breast cancer cell lines with wild-type TP53 (wtTP53). Silencing PFKFB2 significantly inhibited tumor growth and enhanced paclitaxel sensitivity in four xenografts derived from two ovarian and two breast cancer cell lines, and prolonged survival in a triple-negative breast cancer PDX. Transfection of siPFKFB2 increased the glycolysis rate, but decreased the flow of intermediates through the pentose- phosphate pathway in cancer cells with wtTP53, decreasing NADPH. ROS accumulated after PFKFB2 knockdown, which stimulated Jun N-terminal kinase and p53 phosphorylation, and induced apoptosis that depended upon upregulation of p21 and Puma. Conclusions: PFKFB2 is a novel target whose inhibition can enhance the effect of paclitaxel-based primary chemotherapy upon ovarian and breast cancers retaining wtTP53.

Original languageEnglish (US)
Pages (from-to)5702-5716
Number of pages15
JournalClinical Cancer Research
Volume25
Issue number18
DOIs
StatePublished - Sep 15 2019

Fingerprint

Phosphofructokinase-2
Paclitaxel
Fructose
Ovarian Neoplasms
Breast Neoplasms
Heterografts
Cell Line
lissamine rhodamine B
NADP
Reactive Oxygen Species
Neoplasms
Breast
Phosphotransferases
Growth
Puma
Triple Negative Breast Neoplasms
Apoptosis
Pentose Phosphate Pathway
Metabolomics
Glycolysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-2 regulates TP53-dependent paclitaxel sensitivity in ovarian and breast cancers. / Yang, Hailing; Shu, Zhang; Jiang, Yongying; Mao, Weiqun; Pang, Lan; Redwood, Abena; Jeter-Jones, Sabrina L.; Jennings, Nicholas B.; Ornelas, Argentina; Zhou, Jinhua; Rodriguez-Aguayo, Cristian; Bartholomeusz, Geoffrey; Iles, La Kesla R.; Millward, Niki M. Zacharias; Millward, Steven; Lopez, Gabriel; Le, Xiao Feng; Ahmed, Ahmed A.; Piwnica-Worms, Helen; Sood, Anil K; Bast Jr, Robert C; Lu, Zhen.

In: Clinical Cancer Research, Vol. 25, No. 18, 15.09.2019, p. 5702-5716.

Research output: Contribution to journalArticle

Yang, Hailing ; Shu, Zhang ; Jiang, Yongying ; Mao, Weiqun ; Pang, Lan ; Redwood, Abena ; Jeter-Jones, Sabrina L. ; Jennings, Nicholas B. ; Ornelas, Argentina ; Zhou, Jinhua ; Rodriguez-Aguayo, Cristian ; Bartholomeusz, Geoffrey ; Iles, La Kesla R. ; Millward, Niki M. Zacharias ; Millward, Steven ; Lopez, Gabriel ; Le, Xiao Feng ; Ahmed, Ahmed A. ; Piwnica-Worms, Helen ; Sood, Anil K ; Bast Jr, Robert C ; Lu, Zhen. / 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-2 regulates TP53-dependent paclitaxel sensitivity in ovarian and breast cancers. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 18. pp. 5702-5716.
@article{a6d17fc353564a08be8d4ae4275b80a3,
title = "6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-2 regulates TP53-dependent paclitaxel sensitivity in ovarian and breast cancers",
abstract = "Purpose: Paclitaxel is an integral component of primary therapy for breast and epithelial ovarian cancers, but less than half of these cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases. Experimental Design: Twelve kinases that regulate metabolism were depleted in multiple ovarian and breast cancer cell lines to determine whether they regulate sensitivity to paclitaxel in Sulforhodamine B assays. The effects of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2) depletion on cell metabolomics, extracellular acidification rate, nicotinamide adenine dinucleotide phosphate, reactive oxygen species (ROS), and apoptosis were studied in multiple ovarian and breast cancer cell lines. Four breast and ovarian human xenografts and a breast cancer patient-derived xenograft (PDX) were used to examine the knockdown effect of PFKFB2 on tumor cell growth in vivo. Results: Knockdown of PFKFB2 inhibited clonogenic growth and enhanced paclitaxel sensitivity in ovarian and breast cancer cell lines with wild-type TP53 (wtTP53). Silencing PFKFB2 significantly inhibited tumor growth and enhanced paclitaxel sensitivity in four xenografts derived from two ovarian and two breast cancer cell lines, and prolonged survival in a triple-negative breast cancer PDX. Transfection of siPFKFB2 increased the glycolysis rate, but decreased the flow of intermediates through the pentose- phosphate pathway in cancer cells with wtTP53, decreasing NADPH. ROS accumulated after PFKFB2 knockdown, which stimulated Jun N-terminal kinase and p53 phosphorylation, and induced apoptosis that depended upon upregulation of p21 and Puma. Conclusions: PFKFB2 is a novel target whose inhibition can enhance the effect of paclitaxel-based primary chemotherapy upon ovarian and breast cancers retaining wtTP53.",
author = "Hailing Yang and Zhang Shu and Yongying Jiang and Weiqun Mao and Lan Pang and Abena Redwood and Jeter-Jones, {Sabrina L.} and Jennings, {Nicholas B.} and Argentina Ornelas and Jinhua Zhou and Cristian Rodriguez-Aguayo and Geoffrey Bartholomeusz and Iles, {La Kesla R.} and Millward, {Niki M. Zacharias} and Steven Millward and Gabriel Lopez and Le, {Xiao Feng} and Ahmed, {Ahmed A.} and Helen Piwnica-Worms and Sood, {Anil K} and {Bast Jr}, {Robert C} and Zhen Lu",
year = "2019",
month = "9",
day = "15",
doi = "10.1158/1078-0432.CCR-18-3448",
language = "English (US)",
volume = "25",
pages = "5702--5716",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-2 regulates TP53-dependent paclitaxel sensitivity in ovarian and breast cancers

AU - Yang, Hailing

AU - Shu, Zhang

AU - Jiang, Yongying

AU - Mao, Weiqun

AU - Pang, Lan

AU - Redwood, Abena

AU - Jeter-Jones, Sabrina L.

AU - Jennings, Nicholas B.

AU - Ornelas, Argentina

AU - Zhou, Jinhua

AU - Rodriguez-Aguayo, Cristian

AU - Bartholomeusz, Geoffrey

AU - Iles, La Kesla R.

AU - Millward, Niki M. Zacharias

AU - Millward, Steven

AU - Lopez, Gabriel

AU - Le, Xiao Feng

AU - Ahmed, Ahmed A.

AU - Piwnica-Worms, Helen

AU - Sood, Anil K

AU - Bast Jr, Robert C

AU - Lu, Zhen

PY - 2019/9/15

Y1 - 2019/9/15

N2 - Purpose: Paclitaxel is an integral component of primary therapy for breast and epithelial ovarian cancers, but less than half of these cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases. Experimental Design: Twelve kinases that regulate metabolism were depleted in multiple ovarian and breast cancer cell lines to determine whether they regulate sensitivity to paclitaxel in Sulforhodamine B assays. The effects of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2) depletion on cell metabolomics, extracellular acidification rate, nicotinamide adenine dinucleotide phosphate, reactive oxygen species (ROS), and apoptosis were studied in multiple ovarian and breast cancer cell lines. Four breast and ovarian human xenografts and a breast cancer patient-derived xenograft (PDX) were used to examine the knockdown effect of PFKFB2 on tumor cell growth in vivo. Results: Knockdown of PFKFB2 inhibited clonogenic growth and enhanced paclitaxel sensitivity in ovarian and breast cancer cell lines with wild-type TP53 (wtTP53). Silencing PFKFB2 significantly inhibited tumor growth and enhanced paclitaxel sensitivity in four xenografts derived from two ovarian and two breast cancer cell lines, and prolonged survival in a triple-negative breast cancer PDX. Transfection of siPFKFB2 increased the glycolysis rate, but decreased the flow of intermediates through the pentose- phosphate pathway in cancer cells with wtTP53, decreasing NADPH. ROS accumulated after PFKFB2 knockdown, which stimulated Jun N-terminal kinase and p53 phosphorylation, and induced apoptosis that depended upon upregulation of p21 and Puma. Conclusions: PFKFB2 is a novel target whose inhibition can enhance the effect of paclitaxel-based primary chemotherapy upon ovarian and breast cancers retaining wtTP53.

AB - Purpose: Paclitaxel is an integral component of primary therapy for breast and epithelial ovarian cancers, but less than half of these cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases. Experimental Design: Twelve kinases that regulate metabolism were depleted in multiple ovarian and breast cancer cell lines to determine whether they regulate sensitivity to paclitaxel in Sulforhodamine B assays. The effects of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2) depletion on cell metabolomics, extracellular acidification rate, nicotinamide adenine dinucleotide phosphate, reactive oxygen species (ROS), and apoptosis were studied in multiple ovarian and breast cancer cell lines. Four breast and ovarian human xenografts and a breast cancer patient-derived xenograft (PDX) were used to examine the knockdown effect of PFKFB2 on tumor cell growth in vivo. Results: Knockdown of PFKFB2 inhibited clonogenic growth and enhanced paclitaxel sensitivity in ovarian and breast cancer cell lines with wild-type TP53 (wtTP53). Silencing PFKFB2 significantly inhibited tumor growth and enhanced paclitaxel sensitivity in four xenografts derived from two ovarian and two breast cancer cell lines, and prolonged survival in a triple-negative breast cancer PDX. Transfection of siPFKFB2 increased the glycolysis rate, but decreased the flow of intermediates through the pentose- phosphate pathway in cancer cells with wtTP53, decreasing NADPH. ROS accumulated after PFKFB2 knockdown, which stimulated Jun N-terminal kinase and p53 phosphorylation, and induced apoptosis that depended upon upregulation of p21 and Puma. Conclusions: PFKFB2 is a novel target whose inhibition can enhance the effect of paclitaxel-based primary chemotherapy upon ovarian and breast cancers retaining wtTP53.

UR - http://www.scopus.com/inward/record.url?scp=85072233672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072233672&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-3448

DO - 10.1158/1078-0432.CCR-18-3448

M3 - Article

VL - 25

SP - 5702

EP - 5716

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 18

ER -