A Synthetic Analogue of Neopeltolide, 8,9-Dehydroneopeltolide, Is a Potent Anti-Austerity Agent against Starved Tumor Cells.

Haruhiko Fuwa,Mizuho Sato

doi:10.3390/md15100320

Abstract

Neopeltolide, an antiproliferative marine macrolide, is known to specifically inhibit complex III of the mitochondrial electron transport chain (mETC). However, details of the biological mode-of-action(s) remain largely unknown. This work demonstrates potent cytotoxic activity of synthetic neopeltolide analogue, 8,9-dehydroneopeltolide (8,9-DNP), against starved human pancreatic adenocarcinoma PANC-1 cells and human non-small cell lung adenocarcinoma A549 cells. 8,9-DNP induced rapid dissipation of the mitochondrial membrane potential and depletion of intracellular ATP level in nutrient-deprived medium. Meanwhile, in spite of mTOR inhibition under starvation conditions, impairment of cytoprotective autophagy was observed as the lipidation of LC3-I to form LC3-II and the degradation of p62 were suppressed. Consequently, cells were severely deprived of energy sources and underwent necrotic cell death. The autophagic flux inhibited by 8,9-DNP could be restored by glucose, and this eventually rescued cells from necrotic death. Thus, 8,9-DNP is a potent anti-austerity agent that impairs mitochondrial ATP synthesis and cytoprotective autophagy in starved tumor cells.

Highlights

In normal tissues, cells are supplied with sufficient amounts of oxygen and nutrients to maintain homeostasis
Impairment of cytoprotective occurred to the inability ofcytotoxicity cells to lipidate to Mitochondrial inhibitorsautophagy have beenalso reported todue show preferential andLC3-I
Since autophagy is known to be indispensable for cancer cells to survive nutrient-deprived conditions, we investigated whether autophagy is stimulated in starved PANC-1 cells treated with

Summary

Introduction

Cells are supplied with sufficient amounts of oxygen and nutrients to maintain homeostasis. For example, pancreatic tumor cells acquire the ability to tolerate such severe metabolic conditions; more than 50% of human pancreatic adenocarcinoma. PANC-1 cells survived for 48 h in a medium completely deprived of glucose, amino acids, and serum [3]. Normal human fibroblasts and well-differentiated human gastric and liver cancer cells could not survive under the same culture conditions. The tolerability of tumor cells against nutrient deficiency may correlate inversely with their differentiation level. It has been reported that autophagy, a catabolic process that self-digests cytoplasmic components and recycles amino acids as energy source [4,5,6], plays an indispensable role in sustaining survival of tumor cells under nutrient deficient conditions [7,8]. Knockdown of Atg, an autophagy related gene (Atg), by RNA interference significantly increases apoptosis in starved tumor cells [7]

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