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WWP1 inactivation enhances efficacy of PI3K inhibitors while suppressing their toxicities in breast cancer models
Takahiro Kishikawa, … , Yu-Ru Lee, Pier Paolo Pandolfi
Takahiro Kishikawa, … , Yu-Ru Lee, Pier Paolo Pandolfi
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e140436. https://doi.org/10.1172/JCI140436.
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Research Article Cell biology Oncology

WWP1 inactivation enhances efficacy of PI3K inhibitors while suppressing their toxicities in breast cancer models

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Abstract

Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pervasive event in tumorigenesis due to PI3K mutation and dysfunction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Pharmacological inhibition of PI3K has resulted in variable clinical outcomes, however, raising questions regarding the possible mechanisms of unresponsiveness and resistance to treatment. WWP1 is an oncogenic HECT-type ubiquitin E3 ligase frequently amplified and mutated in multiple cancers, as well as in the germ lines of patients predisposed to cancer, and was recently found to activate PI3K signaling through PTEN inactivation. Here, we demonstrate that PTEN dissociated from the plasma membrane upon treatment with PI3K inhibitors through WWP1 activation, whereas WWP1 genetic or pharmacological inhibition restored PTEN membrane localization, synergizing with PI3K inhibitors to suppress tumor growth both in vitro and in vivo. Furthermore, we demonstrate that WWP1 inhibition attenuated hyperglycemia and the consequent insulin feedback, which is a major tumor-promoting side effect of PI3K inhibitors. Mechanistically, we found that AMPKα2 was ubiquitinated and, in turn, inhibited in its activatory phosphorylation by WWP1, whereas WWP1 inhibition facilitated AMPKα2 activity in the muscle to compensate for the reduction in glucose uptake observed upon PI3K inhibition. Thus, our identification of the cell-autonomous and systemic roles of WWP1 inhibition expands the therapeutic potential of PI3K inhibitors and reveals new avenues of combination cancer therapy.

Authors

Takahiro Kishikawa, Hiroshi Higuchi, Limei Wang, Nivedita Panch, Valerie Maymi, Sachem Best, Samuel Lee, Genso Notoya, Alex Toker, Lydia E. Matesic, Gerburg M. Wulf, Wenyi Wei, Motoyuki Otsuka, Kazuhiko Koike, John G. Clohessy, Yu-Ru Lee, Pier Paolo Pandolfi

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Figure 1

PTEN is ubiquitinated and dissociated from the plasma membrane upon treatment with PI3K inhibitors.

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PTEN is ubiquitinated and dissociated from the plasma membrane upon trea...
(A) Evaluation of subcellular localization of PTEN upon BKM120 treatment. Membrane fractions and whole-cell lysate (WCL) were extracted from MDA-MB-231 cells treated with BKM120 over time and subsequently analyzed by WB. EGFR served as a membrane marker and HSP90 as the internal control. (B) Longitudinal subcellular localization of PTEN in MCF7 cells upon treatment with BYL719. LRP6 served as a membrane marker. Blots are from duplicate gels run in parallel. (C) Analysis of PTEN membrane fraction upon treatment with various PI3K inhibitors. MDA-MB-231 cells were treated with the indicated drugs for 48 hours, and membrane and cytosol fractions were extracted. The following doses were used: BKM120 (1.0 μM); BAY80-6946 (1.0 μM); BYL719 (5.0 μM); GDC-0032 (1.0 μM); TGX-221 (5.0 μM). The negative loading control for each fraction is shown in Supplemental Figure 1A as a technical replicate. (D) Analysis of endogenous PTEN ubiquitination over time after BKM120 treatment. Whole lysate was extracted from MDA-MB-231 cells treated with BKM120 for the indicated durations and immunoprecipitated with anti-PTEN beads. Arrow indicates the band with the mouse anti-IgG heavy-chain antibody. Numbers below the blot lanes represent the relative intensities of the PTEN band normalized to the respective loading control. PTEN-Ub(n)/PTEN, relative intensity of polyubiquitinated PTEN normalized to precipitated total PTEN.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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