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<p>We previously demonstrated that the carboline derivative pyra-metho-carnil (PMC) inhibits the proliferation of multiple cancer cell lines. In this study, we investigated the underlying mechanisms by screening for PMC-interacting proteins and testing for effects on protein function. Affinity purification using PMC-immobilized beads followed by gel electrophoresis and mass spectrometry revealed that PMC binds to KDEL receptors (KDELRs), 7-transmembrane proteins regulating the retrieval (retrograde transport) of endoplasmic reticulum (ER)-resident proteins with a C-terminal Lys-Asp-Glu-Lue (KDEL) motif, from the Golgi apparatus. Furthermore, using the Fluoppi system for live-cell imaging, we confirmed that PMC disrupts the interaction between KDELR1 and its ligand BiP. Treatment of HCT116 cells with PMC also disrupted the Golgi localization of GFP-tagged KDELR proteins and promoted the accumulation of misfolded protein aggregates. Indeed, PMC triggered the unfolded protein response (UPR), enhanced CHOP-mediated caspase activation, and reduced viable cell number, suggesting that KDELR inhibition induces proteostatic disruption and leads to apoptotic cell death. Furthermore, PMC sensitized cells to ER stress induced by thapsigargin. Knockdown of KDELR using small interfering (si)RNAs also activated the UPR and suppressed cancer cell proliferation. These findings suggest that PMC inhibits cancer cell proliferation and survival by impairing KDELR function and inducing proteostatic disruption. We propose that KDELR inhibitor drugs may be useful as primary or adjuvant therapeutics for cancer.</p>

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Pyra-metho-carnil disrupts cancer cell proteostasis and induces apoptosis by binding to KDEL receptors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月26日

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  • Kazumasa Yoshida,
  • Kensuke Nishi,
  • Takanori Kitaguchi,
  • Taichi Matsumoto,
  • Gen Maruta,
  • Hisanori Maeoka,
  • Shuhei Ishikura,
  • Senji Shirasawa,
  • Toshiyuki Tsunoda

摘要

We previously demonstrated that the carboline derivative pyra-metho-carnil (PMC) inhibits the proliferation of multiple cancer cell lines. In this study, we investigated the underlying mechanisms by screening for PMC-interacting proteins and testing for effects on protein function. Affinity purification using PMC-immobilized beads followed by gel electrophoresis and mass spectrometry revealed that PMC binds to KDEL receptors (KDELRs), 7-transmembrane proteins regulating the retrieval (retrograde transport) of endoplasmic reticulum (ER)-resident proteins with a C-terminal Lys-Asp-Glu-Lue (KDEL) motif, from the Golgi apparatus. Furthermore, using the Fluoppi system for live-cell imaging, we confirmed that PMC disrupts the interaction between KDELR1 and its ligand BiP. Treatment of HCT116 cells with PMC also disrupted the Golgi localization of GFP-tagged KDELR proteins and promoted the accumulation of misfolded protein aggregates. Indeed, PMC triggered the unfolded protein response (UPR), enhanced CHOP-mediated caspase activation, and reduced viable cell number, suggesting that KDELR inhibition induces proteostatic disruption and leads to apoptotic cell death. Furthermore, PMC sensitized cells to ER stress induced by thapsigargin. Knockdown of KDELR using small interfering (si)RNAs also activated the UPR and suppressed cancer cell proliferation. These findings suggest that PMC inhibits cancer cell proliferation and survival by impairing KDELR function and inducing proteostatic disruption. We propose that KDELR inhibitor drugs may be useful as primary or adjuvant therapeutics for cancer.