Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment

Abstract

The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy-lysosome flux leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR), which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a "double-edged sword" for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that "conventional" agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development strategy has attracted increasing attention because the safety profiles of these medicines are well known. Antimalarial agents such as artemisinin and disease-modifying antirheumatic drug (DMARD) are the typical examples of drug re-positioning which affect the autophagy regulation for the therapeutic use. This review article focuses on recent advances in some of the novel therapeutic strategies that target autophagy with a view to treating/preventing malignant neoplasms.

Keywords: AMPK; Apoptosis; Autophagic cell death; Cancer stem-like cells; Drug re-positioning; Ferroptosis; Nrf2; mTOR signaling; p53; p62/SQSTM1.

Fig. 1

ER stress caused by disruption of autophagy–lysosome flux or conventional chemotherapy confers synergistic therapeutic effects. While p62/SQSTM1 is downregulated during autophagy–lysosome flux, lipidated form of LC-3 (LC-3II) accumulates (lower panel). Obstruction of autophagy flux can be pharmacologically induced by chloroquine, which results in ubiquitination, p62 activation, and LC3-II accumulation (upper panel). Impairment of the autophagy–lysosome pathway induces apoptosis mainly via excessive ER stress. On the other hand, TMZ is an alkylating agent that induces formation of O⁶-methylguanine in DNA, which in turn induces mismatch pair with thymine during the following cycle of DNA replication. Thus, chloroquine and TMZ exhibit the synergistic therapeutic effect for cancer cells

Fig. 2

Nuclear translocation of MiT/TFE protein is responsible for the constitutive activation of autophagy–lysosome pathway in cancer cells. Compared with normal cells, greater amounts of MiT/TFE transcriptional factors (i.e., MITF, TFE3, and TFEB) accumulate in the nuclei of cancer cells under nutrient-insufficient conditions. These transcriptional factors drive expression of genes related to autophagylysosome flux. Surprisingly, even under mTOR-inactivated conditions (such as starvation), cancer cells express high levels of Mit/TFE proteins in the nucleus, which may explain the constitutive activation of autophagy independent of mTOR signaling. Note that the red bar indicates the enhanced autophagic activation, while the blue bar indicates the suppressed autophagic regulation

Fig. 3

CD44 variant-xCT axis-mediated ROS regulation determines the malignant transformation of gastric epithelial cells showing CagA accumulation. Stabilization of xCT (cystine/glutamate antiporter) at the cell membrane in gastric epithelial stem cells due to high CD44v8-10 expression promotes glutathione synthesis, thereby inactivating the Akt signaling pathway. Phosphorylated Akt in CD44v-negative cells induces ubiquitin-proteasome-dependent degradation of p53 in the cytoplasm. Activated Akt signal transduction in non-cancer stem-like cells expressing the standard isoform of CD44 exhibit selective autophagy-mediated degradation of CagA. CagA is translocated from H. pylori via type IV secretion channels, and importantly, accumulation of this pathogenic protein in CD44v-expressing cancer stem-like cells leads to carcinogenesis and maintenance of “stemness.” Note that the red bar shows the relatively high level, while the blue bar indicates the low level

Fig. 4

Capsaicin induces simultaneous autophagic degradation of mutant p53 and reactivation of wild-type p53. Capsaicin activates TRPV1, leading to double-strand DNA breaks and phosphorylation of histone H2AX. ATM kinase phosphorylates and activates a number of DNA repair and checkpoint proteins, including p53, Brca1, and Chk2, ultimately causing cell cycle arrest. On the other hand, capsaicin induces autophagic degradation of p53R175H and p53R273H and reactivates intact p53 that does not harbor mutations in the DNA-binding domain. Thus, expression of apoptotic genes such as Puma, Bax, and DRAM increases