Preventing the unfolded protein response via aberrant activation of 4E-binding protein 1 by versipelostatin
Junichi Matsuo
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550;
Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;
Search for more papers by this authorYoshinori Tsukumo
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550;
Search for more papers by this authorJunko Sakurai
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550;
Search for more papers by this authorSatomi Tsukahara
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550;
Search for more papers by this authorHae-Ryong Park
Department of Food Science and Biotechnology, Kyungnam University 449 Wolyoung-dong, Masan 631-701, Korea;
Search for more papers by this authorKazuo Shin-ya
Biomedical Information Research Center, National Institute of Advanced Industrial Sciences and Technology, 2-42 Aomi, Koto-ku, Tokyo 135-0064, Japan
Search for more papers by this authorToshiki Watanabe
Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;
Search for more papers by this authorTakashi Tsuruo
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550;
Search for more papers by this authorCorresponding Author
Akihiro Tomida
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550;
To whom correspondence should be addressed. E-mail: [email protected]Search for more papers by this authorJunichi Matsuo
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550;
Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;
Search for more papers by this authorYoshinori Tsukumo
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550;
Search for more papers by this authorJunko Sakurai
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550;
Search for more papers by this authorSatomi Tsukahara
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550;
Search for more papers by this authorHae-Ryong Park
Department of Food Science and Biotechnology, Kyungnam University 449 Wolyoung-dong, Masan 631-701, Korea;
Search for more papers by this authorKazuo Shin-ya
Biomedical Information Research Center, National Institute of Advanced Industrial Sciences and Technology, 2-42 Aomi, Koto-ku, Tokyo 135-0064, Japan
Search for more papers by this authorToshiki Watanabe
Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;
Search for more papers by this authorTakashi Tsuruo
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550;
Search for more papers by this authorCorresponding Author
Akihiro Tomida
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550;
To whom correspondence should be addressed. E-mail: [email protected]Search for more papers by this authorAbstract
We recently isolated a macrocyclic compound, versipelostatin (VST), that exerts in vivo antitumor activity. VST shows unique, selective cytotoxicity to glucose-deprived tumor cells by preventing the unfolded protein response (UPR). Here we show that eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of eukaryotic initiation factor 4E-mediated protein translation, plays a role in the UPR-inhibitory action of VST. Indeed, 4E-BP1 is aberrantly activated by VST. This activation occurs specifically during glucose deprivation and results in profound translation repression and prevents induction of the typical UPR markers glucose-regulated protein (GRP) 78 and activating transcription factor (ATF) 4. Our overexpression and knockdown experiments showed that 4E-BP1 can regulate GRP78 and ATF4 expression. These mechanisms appear to be specific for VST. By contrast, rapamycin, which activates 4E-BP1 regardless of cellular glucose availability, has only marginal effects on the expression of GRP78 and ATF4. Our present findings demonstrate that aberrant 4E-BP1 activation can contribute to UPR preventing by VST, possibly through a mechanism that does not operate in rapamycin-treated cells. (Cancer Sci 2009; 100: 327–333)
References
- 1 Brown JM, Giaccia AJ. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 1998; 58: 1408–16.
- 2 Scrivaen P, Brown NJ, Pockley AG, Wyld L. The unfolded protein response and cancer: a brighter future unfolding? J Mol Med 2007; 85: 331–41.
- 3 Zhao L, Ackerman SL. Endoplasmic reticulum stress in health and disease. Curr Opin Cell Biol 2006; 18: 1–9.
- 4 Ma Y, Hendershot LM. The role of the unfolded protein response in tumor development: friend or foe? Nat Rev Cancer 2004; 4: 966–77.
- 5 Lee AS. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res 2007; 67: 3496–9.
- 6 Lee E, Nichols P, Spicer D, Groshen S, Yu MC, Lee AS. GRP78 as a novel predictor of responsiveness to chemotherapy in breast cancer. Cancer Res 2007; 66: 7849–53.
- 7 Pyrko P, Schonthal AH, Hofman FM, Chen TC, Lee AS. The unfolded protein response regulator GRP78/BiP as a novel target for increasing chemosensitivity in malignant gliomas. Cancer Res 2007; 67: 9809–16.
- 8 Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8: 519–29.
- 9 Marciniak SJ, Ron D. Endoplasmic reticulum stress signalling in disease. Physiol Rev 2006; 86: 1133–49.
- 10 Dong D, Ni M, Li J et al . Critical role in the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res 2008; 68: 498–505.
- 11 Bi M, Naczki C, Koritzinsky M et al . ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J 2005; 24: 3470–81.
- 12 Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 2000; 5: 897–04.
- 13 Marciniak SJ, Yun CY, Oyadomari S et al . CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 2004; 18: 3066–77.
- 14 Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic reticulum-resident kinase. Nature 1999; 397: 271–4.
- 15 Harding HP, Novoa I, Zhang Y et al . Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000; 6: 1099–08.
- 16 Ma Y, Hendershot LM. Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress. J Biol Chem 2003; 278: 34 864–73.
- 17 Kojima E, Takeuchi A, Haneda M et al . The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress-elucidation by GADD34-deficient mice. FASEB J 2003; 17: 1573–5.
- 18 Novoa I, Zhang Y, Zeng H, Jungreis R, Harding HP, Ron D. Stress-induce gene expression requires programmed recovery from translational repression. EMBO J 2003; 22: 1180–7.
- 19 Graff JR, Konicek BW, Carter JH, Marcusson EG. Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res 2008; 68: 631–4.
- 20 Polunovsky VA, Bitterman PB. The cap-dependent translation apparatus integrates and amplifies cancer pathway. RNA Biol 2006; 3: 10–17.
- 21 Dever TE. Gene-specific regulation by general translation factors. Cell 2002; 108: 545–56.
- 22 Gingras A, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001; 15: 807–26.
- 23 Gingras A, Gygi SP, Raught B et al . Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev 1999; 13: 1422–37.
- 24 Fels DR, Koumenis C. The PERK/eIF2α/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biol Ther 2006; 5: 723–8.
- 25 Park H, Tomida A, Sato S et al . Effect on tumor cells of blocking survival response to glucose deprivation. J Natl Cancer Inst 2004; 96: 1300–10.
- 26 Horie K, Tomida A, Sugimoto Y et al . SUMO-1 conjugation to intact DNA topoisomerase I amplifies cleavable complex formation induced by camptothecin. Oncogene 2002; 21: 7913–22.
- 27 Polunovsky VA, Gingras A, Sonenberg N et al . Translational control of the antiapoptotic function of Ras. J Biol Chem 2000; 275: 24 776–80.
- 28 Tsukumo Y, Akihiro T, Kitahara O. Nucleobindin 1 controls the unfolded protein response by inhibiting ATF6 activation. J Biol Chem 2007; 282: 29 264–72.
- 29 Arsham AM, Howell JJ, Simon MC. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J Biol Chem 2003; 32: 29 655–60.
- 30 Denizot F, Lang R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Meth 1986; 89: 271–7.
- 31 Yamaguchi Y, Ishihara H, Yamada T et al . ATF4-mediated induction of 4E-BP1 contributes to pancreatic β cell survival under endoplasmic reticulum stress. Cell Metab 2008; 7: 269–76.
- 32 Koritzinsky M, Magagnin MG, Beucken T et al . Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J 2006; 25: 1114–25.
- 33 Hudes G, Carducci M, Tomczak P et al . Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356: 2271–81.
- 34 Motzer R, Escudier B, Oudard S et al . Efficiency of everolimus in advanced renal cell carcinoma: a double-blind, randomized, placebo-controlled phase III trial. Lancet 2008; 372: 449–56.
- 35 Gridelli C, Maione P, Rossi A. The potential role of mTOR inhibitors in non-small cell lung cancer. Oncologist 2007; 13: 139–47.
