Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment

Abstract

Induction of cell death and inhibition of cell survival are the main principles of cancer therapy. Resistance to chemotherapeutic agents is a major problem in oncology, which limits the effectiveness of anticancer drugs. A variety of factors contribute to drug resistance, including host factors, specific genetic or epigenetic alterations in the cancer cells and so on. Although various mechanisms by which cancer cells become resistant to anticancer drugs in the microenvironment have been well elucidated, how to circumvent this resistance to improve anticancer efficacy remains to be defined. Autophagy, an important homeostatic cellular recycling mechanism, is now emerging as a crucial player in response to metabolic and therapeutic stresses, which attempts to maintain/restore metabolic homeostasis through the catabolic lysis of excessive or unnecessary proteins and injured or aged organelles. Recently, several studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy of these drugs as well as drug resistance. Thus, understanding the novel function of autophagy may allow us to develop a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in the treatment of cancer patients.

Figure 1

A summary of the approaches by which cancer cells become resistant to chemotherapy and various kinds of genotoxic or metabolic stresses

Figure 2

Interrelations between autophagy-related signaling and cell growth control in response to stress. Autophagy can be activated in response to multiple stresses during cancer progression, including nutrient deprivation, endoplasmic reticulum stress, hypoxia, glucose/energy depletion, chemotherapy and other diverse stresses. The AMPK/mTOR pathway functions as a central conduit for autophagic signaling pathways to promote cell survival or death

Figure 3

Dual role of autophagy for therapeutic purposes in cancer. On one hand, autophagy is activated as a protective mechanism to mediate the acquired resistance phenotype of some cancer cells during chemotherapy. On the other hand, autophagy may also function as a death executioner to induce autophagic cell death, a form of physiological cell death that is contradictory to apoptosis

Figure 4

The molecular mechanisms of autophagy activation in response to chemotherapeutic agents. The activation of autophagy either leads to cancer cell chemoresistance via EGFR signaling, PI3K/AKT/ mTOR pathways, p53, VEGF, MAPK14/p38α signaling and microRNA or potentiates autophagic cell death through AMPK/AKT1/mTOR axis, which depends on the tumor types and treatment characteristic