Malformin A1 treatment alters invasive and oncogenic phenotypes of human colorectal cancer cells through stimulation of the p38 signaling pathway

Abstract

Malformin A1 (MA1), a cyclic pentapeptide isolated from Aspergillus niger, has been found to possess a range of bioactive properties including antibacterial activity. However, it is unclear whether MA1 exerts an anticancer effect or not. In this study, we conducted in vitro experiments to investigate its anticancer properties in human colorectal cancer cells. The effect of MA1 on human colorectal cancer cells, SW480 and DKO1, was examined by the WST-1 cell viability assay, inverted microscopy, 5-bromo-2-deoxyuridine (BrdU) incorporation, flow cytometry, DNA fragmentation, wound healing, Transwell assays, and western blotting. MA1 treatment showed potent cytotoxic activities on human colorectal cancer cells. MA1 treatment induced apoptosis by activating the poly(ADP-ribose) polymerase (PARP), caspase‑3, -7, and -9. MA1 treatment led to the increase in p53 upregulated modulator of apoptosis (PUMA) and the decrease in X-linked inhibitor of apoptosis protein (XIAP) and Survivin. In addition, MA1 treatment induced cell cycle arrest in the sub-G1 phase. The pan-caspase inhibitor, Z‑VAD‑FMK, attenuated these MA1-induced apoptotic effects on human colorectal cancer cells. Moreover, MA1 treatment suppressed tumor cell migration and invasion. The phosphorylation level of p38 was upregulated by MA1 treatment, and the inhibitor of p38, SB203580, attenuated the MA1-induced p38 phosphorylation as well as caspase‑3 and PARP activation. These results indicate that MA1 treatment alters invasive and oncogenic phenotypes of human colorectal cancer cells through the stimulation of the p38 signaling pathway.

Safety of the fungal workhorses of industrial biotechnology: update on the mycotoxin and secondary metabolite potential of Aspergillus niger, Aspergillus oryzae, and Trichoderma reesei

“…Furthermore, malformins have never been detected after mycotoxicosis caused by A. niger . Malformins are very promising anti-cancer agents, however (Park et al 2017b ).…”

A comprehensive review of microorganism‐derived cyclic peptides: Bioactive functions and food safety applications

“…For instance, Park et al. (2017) investigated the cytotoxicity of malformin A1 (MA1), a cyclic pentapeptide from Aspergillus niger. And it has been found that MA1 displays potent cytotoxicity toward various cancer cell lines.…”

“…Cyclic peptides are cyclic compounds formed by either proteinogenic or nonproteinogenic amino acids along with the amide bonds between them (Xiaohan et al, 2017). Currently, cyclic peptides have been found in various sources, including plants (de Veer et al, 2019), mammals (Falanga et al, 2017), fungi (Bilal et al, 2018;Liang et al, 2017;Liddicoat & Lavelle, 2019;Park et al, 2017), bacteria (Karanam et al, 2020;Li et al, 2020;Ling et al, 2015;Wang et al, 2022), and actinomycetes (Byun et al, 2020;Jiang et al, 2021;Nalli et al, 2017;Shin et al, 2018;Song et al, 2019). Cyclic peptides overcome most of the disadvantages of their linear counterparts and exhibit higher F I G U R E 1 Overview of synthesis, biological mechanisms, and food safety applications in microorganism-derived cyclic peptides metabolic stability, membrane permeability, and oral bioavailability.…”

Natural Cyclopeptides as Anticancer Agents in the Last 20 Years

“…In addition, stimulation of the AMP-activated serine/threonine protein kinase/mammalian target-of-rapamycin (AMPK/mTOR) pathway by adding oxidative stress or decreasing ATP could lead to MA 1 -mediated autophagy [299]. In human colorectal cancer cells (SW480 and DKO1), invasive and oncogenic phenotypes were modified through p38 signaling pathway [300]. Recently, the marine-derived fungus A. tubingenesis also yielded MA 1 with significant cytotoxicity against HeLa (IC 50 = 9.48 nM) and P388 (IC 50 = 132.9 nM) cell lines [301].…”