Human dynactin-associated protein transforms NIH3T3 cells to generate highly vascularized tumors with weak cell-cell interaction

Tatsuki Kunoh, Weixiang Wang, Hiroaki Kobayashi, Daisuke Matsuzaki, Yuki Togo, Masahiro Tokuyama, Miho Hosoi, Koichi Koseki, Shu Ichi Wada, Nobuo Nagai, Toshinobu Nakamura, Shintaro Nomura, Makoto Hasegawa, Ryuzo Sasaki, Tamio Mizukami

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Abstract

Human dynactin-associated protein (dynAP) is a transmembrane protein that promotes Akt-Ser473 phosphorylation. Here, we report the oncogenic properties of dynAP. In contrast to control NIH3T3 cells expressing LacZ (NIH3T3LacZ), NIH3T3dynAP cells vigorously formed foci in two-dimensional culture, colonies on soft agar, and spheroids in anchoragedeficient three-dimensional culture. NIH3T3dynAP cells injected into nude mice produced tumors with abundant blood vessels and weak cell-cell contacts. Expression of dynAP elevated the level of rictor (an essential subunit of mTORC2) and promoted phosphorylation of FOXO3aSer253. FOXO3a is a transcriptional factor that stimulates expression of pro-apoptotic genes and phosphorylation of FOXO3a abrogates its function, resulting in promoted cell survival. Knockdown of rictor in NIH3T3dynAP cells reduced AktSer473 phosphorylation and formation of foci, colony in soft agar and spheroid, indicating that dynAP-induced activation of the mTORC2/AktSer473 pathway for cell survival contributes to cell transformation. E-cadherin and its mRNA were markedly reduced upon expression of dynAP, giving rise to cells with higher motility, which may be responsible for the weak cell-cell adhesion in tumors. Thus, dynAP could be a new oncoprotein and a target for cancer therapy.

Original languageEnglish
Article numbere0135836
JournalPloS one
Volume10
Issue number8
DOIs
Publication statusPublished - Aug 18 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Kunoh, T., Wang, W., Kobayashi, H., Matsuzaki, D., Togo, Y., Tokuyama, M., Hosoi, M., Koseki, K., Wada, S. I., Nagai, N., Nakamura, T., Nomura, S., Hasegawa, M., Sasaki, R., & Mizukami, T. (2015). Human dynactin-associated protein transforms NIH3T3 cells to generate highly vascularized tumors with weak cell-cell interaction. PloS one, 10(8), [e0135836]. https://doi.org/10.1371/journal.pone.0135836