Peneciraistin C induces caspase‐independent autophagic cell death through mitochondrial‐derived reactive oxygen species production in lung cancer cells

Abstract

Peneciraistin C (Pe-C) is a novel spiroketal compound isolated from the saline soil derived fungus Penicillium raistrickii. Our previous study showed that Pe-C exerted a potent cytotoxic effect on many kinds of cancer cell lines, especially on human lung cancer A549 cells. Here, we report the anticancer mechanisms of Pe-C in a variety of lung cancer cells. The results showed that Pe-C induced caspase-independent autophagic cell death and elevated mitochondrial-derived reactive oxygen species levels. Interestingly, if autophagy was blocked by 3-methyladenine or Atg5 siRNA, Pe-C triggered a shift from autophagic cell death into caspase-dependent apoptotic cell death. In addition, cotreatment with the antioxidant N-acetyl-L-cysteine or Mito-TEMPO could effectively reverse the effect of the enhanced reactive oxygen species production, which in turn almost completely prevented the cell death induced by Pe-C. Thus, this study provided new insights into the mechanisms underlying Pe-C-mediated cell death, which indicated that Pe-C could be a potential drug candidate for therapy of lung cancers. (Cancer Sci 2013; 104: 1476-1482 L ung cancer is the leading cause of cancer-related death in men and is second only to breast cancer in women.(1,2) In China, approximately 60 0000 people suffer from this disease and consequently die each year. In clinical practice, lung carcinomas are classified into two major types: non-small-cell lung cancer and small-cell lung cancer.(3) Chemotherapy is still an important option in curing or controlling lung cancer. Although many relatively effective chemotherapeutic agents have been developed, the cure rate of lung cancer is still low because of drug resistance. In addition, the side-effects of chemotherapeutic drugs often hamper the quality of life of lung cancer patients.(4) Therefore, the discovery of effective novel molecular targeted therapies for lung cancer is urgently needed.Spiroketals are cyclic substructures found in many natural products that show a wide range of biological activities, such as antitumor activity, antibacterial activity, and anti-inflammatory effects.(5-8) Peneciraistin C (Pe-C) (Fig. 1) is a novel spiroketal compound purified from the fungus Penicillium raistrickii, isolated from saline soil collected in Bohai Bay in Zhanhua (Shandong Province, China). In preliminary screening, Pe-C showed potent cytotoxic activity in many kinds of human cancer cell lines, especially in human lung cancer A549 cells. (9) In this study, we report the antitumor activity and the possible molecular mechanisms of Pe-C in a variety of lung cancer cells.Over the past decades, apoptosis induction is the main focus in the development of new anticancer drugs, so a great number of studies have been focused on type-I programmed cell death. In contrast, more and more evidence now shows that autophagic cell death has emerged as an important mechanism of cancer cell death induced by anticancer agents.(10-12) The housekeeping role of autophagy is to protect cells under stressful conditions throug...

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