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PRKCSH contributes to TNFSF resistance by extending IGF1R half-life and activation in lung cancer

Gu-Choul Shin1,2, Hyeong Min Lee3,4, Nayeon Kim5

  • 1Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, 16419, Republic of Korea. rnelr@naver.com.

Experimental & Molecular Medicine
|January 10, 2024
PubMed

Insights

Protein kinase C substrate 80K-H (PRKCSH) promotes lung cancer growth by activating IGF1R, causing resistance to tumor necrosis factor superfamily (TNFSF) therapies. Targeting PRKCSH may enhance natural killer (NK) cell cancer treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Tumor necrosis factor superfamily (TNFSF) resistance is a significant challenge in cancer therapy.
  • Tumor-intrinsic mechanisms driving TNFSF resistance are not fully understood.
  • Identifying novel targets is crucial for overcoming therapeutic resistance.

Purpose of the Study:

  • To investigate the role of protein kinase C substrate 80K-H (PRKCSH) in TNFSF resistance in lung cancer.
  • To elucidate the molecular mechanisms by which PRKCSH contributes to cancer progression and therapy resistance.
  • To evaluate PRKCSH as a potential therapeutic target for enhancing natural killer (NK) cell-based cancer immunotherapy.

Main Methods:

  • Analysis of PRKCSH and IGF1R expression in lung cancer tissues.
  • Biochemical assays to determine the interaction between PRKCSH and IGF1R.
  • Cellular assays to assess the impact of the PRKCSH-IGF1R axis on apoptosis and survival pathways (caspase-8, Mcl-1, caspase-9).
  • In vivo studies using a tumor xenograft mouse model to evaluate the effect of PRKCSH deficiency on NK cell-mediated antitumor activity.

Main Results:

  • PRKCSH abundance in lung cancer correlates with increased Insulin-like Growth Factor 1 Receptor (IGF1R) activation.
  • PRKCSH directly interacts with IGF1R, prolonging its half-life and boosting oncogenic signaling.
  • The PRKCSH-IGF1R axis inhibits key apoptosis pathways (caspase-8, caspase-9) and promotes survival (Mcl-1 expression).
  • PRKCSH deficiency enhances the efficacy of natural killer (NK) cells against tumors in a mouse model.

Conclusions:

  • PRKCSH is a key mediator of TNFSF resistance in lung cancer by promoting IGF1R activation and inhibiting apoptosis.
  • The PRKCSH-IGF1R pathway represents a novel mechanism of tumor-intrinsic resistance to TNFSF signaling.
  • Targeting PRKCSH holds promise for improving the effectiveness of NK cell-based immunotherapies in cancer treatment.

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