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 - Zacharias, Niki M.
AU - Millward, Steven W.
AU - Lopez-Berestein, Gabriel
AU - Le, Xiao Feng
AU - Ahmed, Ahmed A.
AU - Piwnica-Worms, Helen
AU - Sood, Anil K.
AU - Bast, Robert C.
AU - Lu, Zhen
N1 - Funding Information:
This work was supported by the Cancer Prevention and Research Institute of Texas RP110595-P1, the MD Anderson SPOREs in Ovarian Cancer NCI P50 CA 083639 and CA 217685, the Shared Resources of the MD Anderson CCSG grant NCI P30 CA016672, R35 CA209904, the American Cancer Society Research Professor Award, the Frank McGraw Memorial Chair in Cancer Research, The National Foundation for Cancer Research, the philanthropic support from generous donations from Stuart and Gaye-Lynn Zarrow, the Mossy Foundation, and the Roberson Endowment. A.A. Ahmed is supported by grants from the NIHR National Institute for Health Research Oxford Biomedical Research Centre and Ovarian Cancer Action. We also acknowledge grants R21CA181994 and R25T CA557730.
Publisher Copyright:
© 2019 American Association for Cancer Research.
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.
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U2 - 10.1158/1078-0432.CCR-18-3448
DO - 10.1158/1078-0432.CCR-18-3448
M3 - Article
C2 - 31391192
AN - SCOPUS:85072233672
SN - 1078-0432
VL - 25
SP - 5702
EP - 5716
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -