EGFR Family Members' Regulation of Autophagy Is at a Crossroads of Cell Survival and Death in Cancer

Abstract

The epidermal growth factor receptor (EGFR) signaling pathways are altered in many cancers contributing to increased cell survival. These alterations are caused mainly through increased expression or mutation of EGFR family members EGFR, ErbB2, ErbB3, and ErbB4. These receptors have been successfully targeted for cancer therapy. Specifically, a monoclonal antibody against ErbB2, trastuzumab, and a tyrosine kinase inhibitor against EGFR, gefitinib, have improved the survival of breast and lung cancer patients. Unfortunately, cancer patients frequently become resistant to these inhibitors. This has led to investigating how EGFR can contribute to cell survival and how cancer cells can overcome inhibition of its signaling. Indeed, it is coming into focus that EGFR signaling goes beyond a single signal triggering cell proliferation and survival and is a sensor that regulates the cell's response to microenvironmental stresses such as hypoxia. It acts as a switch that modulates the ability of cancer cells to survive. Autophagy is a process of self-digestion that is inhibited by EGFR allowing cancer cells to survive under stresses that would normally cause death and become resistant to chemotherapy. Inhibiting EGFR signaling allows autophagy to contribute to cell death. This gives new opportunities to develop novel therapeutic strategies to treat cancers that rely on EGFR signaling networks and autophagy. In this review, we summarize the current understanding of EGFR family member regulation of autophagy in cancer cells and how new therapeutic strategies could be developed to overcome drug resistance.

Keywords: autophagy; beclin-1; epidermal growth factor; mitochondria; signaling.

Figure 1

EGFR family members contribute to cell survival through multiple mechanisms. EGFR family members activate three of the major signaling pathways for cell survival including the RAS/MAPK pathway, the JAK/STAT pathway, and the PI3K/AKT pathway. Downstream signaling increases transcription levels of survival proteins, including Mcl-1 and Elk-1. It has also been shown that EGFR can translocate directly to the nucleus and activate transcription of survival genes. Finally, equilibrium between recycling EGFR back to the cell surface and sending it to the lysosome for degradation balances continued signaling.

Figure 2

Stages of Autophagy. Upon induction of autophagy, the class III PI3K complex binds to beclin 1 forming the preautophagosome from the phagophore. Cytosolic LC3-1 is cleaved and lipidated to form LC3-II, which goes to the membrane of the autophagosome and leads to fusion of the autophagosome and the lysosome to form the autolysosome and subsequent breakdown of the vesicle and its contents.

Figure 3

EGFR family members regulate autophagy affecting cancer cell survival and death. EGF receptor family members interact with key proteins in the autophagic pathway, leading to both cell survival and cell death dependent on the context. This includes activation of the mTOR pathway, leading to inhibition of the ULK1 complex, the binding of EGFR family members to beclin-1, and EGFR binding to LAPTM4B, releasing beclin-1 from Rubicon. The context of these interactions determines the level of autophagy, which is often dysregulated in cancer.