The Role of mTORC1 Pathway and Autophagy in Resistance to Platinum-Based Chemotherapeutics

Abstract

Cisplatin (cis-diamminedichloroplatinum I) is a platinum-based drug, the mainstay of anticancer treatment for numerous solid tumors. Since its approval by the FDA in 1978, the drug has continued to be used for the treatment of half of epithelial cancers. However, resistance to cisplatin represents a major obstacle during anticancer therapy. Here, we review recent findings on how the mTORC1 pathway and autophagy can influence cisplatin sensitivity and resistance and how these data can be applicable for the development of new therapeutic strategies.

Keywords: anticancer drug resistance; autophagy; cisplatin; mTORC1 pathway.

Figure 1

Cancers where cisplatin is used as a mainstream drug.

Figure 2

Main factors of cisplatin resistance. Cancer cells can develop resistance to cisplatin via decreased drug influx or increased efflux, because of the drug inactivation through the interaction with glutathione (GSH) and metallothioneins (MT), because of enhanced DNA damage response and alternations in signaling pathways.

Figure 3

Cisplatin and its derivatives used in the treatment of different types of cancers. Side effects for each drug are listed.

Figure 4

Overview of mTORC1 signaling.

Figure 5

mTORC1 pathway factors and effectors involved in cisplatin resistance. The factors and effectors of the same signaling path are indicated with the same color. EIF3A translational factor negatively regulates mTORC1 activity. Accordingly, EIF3A downregulation (black arrow) increases mTORC1 activity. The activation of p70S6K by mTORC1 can be suppressed by RAME. Many oncogenic mutations have been detected in eukaryotic translation initiation factors, a group of mTORC1 downstream effectors. In addition, PDCD4, which is not a direct target of mTORC1, can suppress protein translation by interacting with EIF4A and EIF4G to inhibit the formation of the translation initiation complex. A knockdown of PDCD4 (black arrow) reduces sensitivity to platinum drugs. BCAT1 overexpression results in a decrease of leucine and other branched-chain amino acid levels. As a consequence, mTORC1 cannot be effectively activated (dashed arrow), resulting in enhanced autophagy and cisplatin resistance. NPRL2 downregulation (white arrow) results in mTORC1 activation, compromised DNA damage response and cisplatin resistance. See text for more details. RAGD promotes TFEB inhibition through its phosphorylation by mTORC1 and sequestration in the cytoplasm, where TFEB cannot exert its function as a transcription factor. Cisplatin treatment induces TFEB nuclear translocation and activation. Active TFEB increases the expression of programmed cell death-ligands 1 and 2 (PD-L1 and PD-L2) to foster an immunosuppressive tumor microenvironment that mediates drug resistance. The suppression of TFEB inhibits the expression of the copper transporter ATP7B involved in cisplatin efflux and sensitizes initially resistant ovarian cancer cells to cisplatin.

Figure 6

Main factors of autophagy involved in cisplatin resistance. HQ/CQ: chloroquine and hydroxychloroquine.