GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer

Kenneth L. Scott, Omar Kabbarah, Mei-Chih Liang, Elena Ivanova, Valsamo Anagnostou, Joyce Wu, Sabin Dhakal, Min Wu, Shujuan Chen, Tamar Feinberg, Joseph Huang, Abdel Saci, Hans R. Widlund, David E. Fisher, Yonghong Xiao, David L. Rimm, Alexei Protopopov, Kwok-Kin Wong and Lynda Chin ()
Additional contact information
Kenneth L. Scott: Department of Medical Oncology,
Omar Kabbarah: Department of Medical Oncology,
Mei-Chih Liang: Department of Medical Oncology,
Elena Ivanova: Belfer Institute for Applied Cancer Science,
Valsamo Anagnostou: Yale University School of Medicine, New Haven, Connecticut 06520, USA
Joyce Wu: Department of Medical Oncology,
Sabin Dhakal: Department of Medical Oncology,
Min Wu: Department of Medical Oncology,
Shujuan Chen: Department of Medical Oncology,
Tamar Feinberg: Department of Medical Oncology,
Joseph Huang: Department of Medical Oncology,
Abdel Saci: Harvard Medical School
Hans R. Widlund: Dana-Farber Cancer Institute
David E. Fisher: Dana-Farber Cancer Institute
Yonghong Xiao: Belfer Institute for Applied Cancer Science,
David L. Rimm: Yale University School of Medicine, New Haven, Connecticut 06520, USA
Alexei Protopopov: Belfer Institute for Applied Cancer Science,
Kwok-Kin Wong: Department of Medical Oncology,
Lynda Chin: Department of Medical Oncology,

Nature, 2009, vol. 459, issue 7250, 1085-1090

Abstract: Abstract Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in several solid tumour types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to target of rapamycin (TOR) signalling. Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR (also known as FRAP1) signalling in human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus, genomic and genetic, biological, functional and biochemical data in yeast and humans establishes GOLPH3 as a new oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to rapamycin, a cancer drug in clinical use.

Date: 2009
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DOI: 10.1038/nature08109

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