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Jiani Ye
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MA01 - Novel Systemic Treatment in NSCLC (ID 102)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 11:45 - 12:45, Scientific Program Auditorium
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MA01.11 - CD47 Agonist Peptide PKHB1 Induced Cell Death in NSCLC via Triggering Endoplasmic Reticulum Stress (ID 1141)
11:45 - 12:45 | Presenting Author(s): Jiani Ye
- Abstract
- Presentation
Introduction
CD47 is a transmembrane glycoprotein highly expressed on the surface of tumor cells. Previous studies have reported that CD47-SIRP α signaling complex could generate tumor immune escape and exist other signal pathway involved in the regulations of CD47 in tumor growth and metastasis, but the potential mechanisms are still barely understood. PKHB1, the first described serum-stable CD47 agonist peptide, has shown some pretty promising results in triggering cell death, such as leukemic cells. Here, we aimed to study the potential biological function of PKHB1 and its molecular mechanism in NSCLC.
Methods
The mRNA and protein expression of CD47 in NSCLC cell lines were determined by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry, respectively. NSCLC cell lines were treated with PKHB1 at different concentrations for 2 hours and then we assessed cell proliferation, cell death, mitochondrial membrane potential, and intracellular calcium release. Western blot analysis was performed to detect the expression of proteins related to apoptosis and endoplasmic reticulum stress. The anti-tumor efficacy in vivo of PKHB1 was investigated in tumor-bearing mice.
Results
First, we observed that CD47 was overexpressed in NSCLC cell lines. Then the results showed that PKHB1 significantly suppressed NSCLC cell proliferation, and induced cell death in a dose-dependent manner. Importantly, we found that PKHB1 treatment triggered mitochondrial transmembrane potential depolarization and Ca2+ overloading. Meanwhile, western blot analysis demonstrated that PKHB1 increased Bax, caspase-9 and cleavage of PARP activities and decreased Bcl-2 activity. Further study revealed that PKHB1 markedly promoted the expression of endoplasmic reticulum stress-related proteins, upregulated the phosphorylation levels of PERK and eIF2α, the expressions of ATF4, IRE1, XBP1 and ATF6, as well as increased the activation of CHOP and JNK pathways. Moreover, we observed PKHB1 could notably inhibit NSCLC tumor growth in vivo.
Conclusion
CD47 agonist peptide PKHB1 induced cell death in NSCLC via triggering endoplasmic reticulum stress, and may be a promising peptide-based therapeutic target for NSCLC.
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