Abstract
BackgroundAutophagy is an intracellular process through which intracellular components are recycled in response to nutrient or growth factor deficiency to maintain homeostasis. We identified the peptide autophagy-related cancer-suppressing peptide (ARCSP), a potential antitumor peptide that disrupts intracellular homeostasis by blocking autophagic flux and causes cytotoxic death.MethodsThe proliferative ability of ARCSP-treated cervical cancer cells was examined by the CCK8, EdU, and colony formation assays. The TUNEL assay was used to detect apoptosis. Mitochondrial function was evaluated based on the mitochondrial membrane potential. Autophagic flux was detected by immunofluorescence and confocal microscopy. The autophagy-related proteins AMPK, Raptor, mTOR, p62, LC3B, atg7, Rab7, LAMP1, LAMP2, and cathepsin D were detected by Immunoblotting. The antitumor effect of ARCSP was explored in vivo by establishing a transplant tumor model in nude mice.ResultsThe results demonstrated that ARCSP induced cell death and inhibited proliferation. ARCSP induced AMPK/mTOR activation, resulting in the accumulation of the proteins LC3B, p62 and Atg7. ARCSP also blocked autophagosome-lysosome fusion by inhibiting endosomal maturation and increasing the lysosomal pH. The accumulation of nonfused autophagosomes exacerbated cytotoxic death, whereas knocking down Atg7 reversed the cytotoxic death induced by ARCSP. ARCSP-treated cells exhibited increased cytotoxic death after cotreatment with an autophagy inhibitor (Chloroquine CQ). Furthermore, the tumors of ARCSP-treated nude mice were significantly smaller than those of untreated mice.ConclusionsOur findings demonstrate that ARCSP, a novel lethal nonfused autophagosome inducer, might cause mitochondrial dysfunction and autophagy-related cytotoxic death and is thus a prospective agent for cancer therapy.
Highlights
Autophagy is an intracellular process through which intracellular components are recycled in response to nutrient or growth factor deficiency to maintain homeostasis
We found for the first time that the peptide at m/z 6432 Da can inhibit the proliferation of cervical cancer cells by regulating autophagy; we temporarily named the peptide at m/z 6432 Da autophagy-related tumor suppressor peptide (ARCSP)
autophagyrelated cancer-suppressing peptide (ARCSP) inhibits the proliferation of cervical cancer cells and has low cytotoxicity in normal cells To study the effects of ARCSP on the growth of human cervical cancer cells, we used HCerEpiC, LO-2, HeLa and CaSki cells
Summary
Autophagy is an intracellular process through which intracellular components are recycled in response to nutrient or growth factor deficiency to maintain homeostasis. The levels of the peptide at m/z 6432 Da are significantly reduced in the serum of non-small cell lung cancer [7], papillary thyroid carcinoma [8], triple negative breast cancer [9], and nephroblastoma [4, 10] patients compared to normal controls, indicating that it may be a potential biomarker for tumors. These specific protein markers play an important role in the diagnosis and treatment of malignant tumors [11]. We further explored the relationship between ARCSP-induced cell death and autophagy
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