Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells

Abstract

Macroautophagy/autophagy inhibition is a novel anticancer therapeutic strategy, especially for tumors driven by mutant RAS. Here, we demonstrate that autophagy inhibition in RAS-mutated cells induces epithelial-mesenchymal transition (EMT), which is associated with enhanced tumor invasion. This is at least partially achieved by triggering the NFKB/NF-κB pathway via SQSTM1/p62. Knockdown of ATG3 or ATG5 increases oncogenic RAS-induced expression of ZEB1 and SNAI2/Snail2, and activates NFKB activity. Depletion of SQSTM1 abolishes the activation of the NFKB pathway induced by autophagy inhibition in RAS-mutated cells. NFKB pathway inhibition by depletion of RELA/p65 blocks this EMT induction. Finally, accumulation of SQSTM1 protein correlates with loss of CDH1/E-cadherin expression in pancreatic adenocarcinoma. Together, we suggest that combining autophagy inhibition with NFKB inhibitors may therefore be necessary to treat RAS-mutated cancer.

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

“…(Macro) autophagy is where a double-membraned vesicle is formed, which captures material in the cytoplasm to be degraded, whereas selective autophagy specifically targets cargo to be degraded [12][13][14][15] . Autophagy has also been proposed to have roles in a number of diseases [16] , such as fibrosis [17][18][19] , neurodegeneration [20] and cancer [21,22] [ Figure 2].…”

“…Numerous studies in different contexts have demonstrated interactions between autophagy and EMT, although it does appear this is both context-and tissue-dependent [ Table 1]. Studies have shown that manipulation of autophagy can promote EMT, invasion and metastasis [21,27,[38][39][40] ; these have been demonstrated in a wide variety of tissues/cell lines including pancreatic, breast, colorectal, melanoma and gastric. In total, 1400 tumours from 20 different types of cancers were analysed for LC3B, an autophagy marker, and it was found that increased expression was associated with metastasis and invasion [27] .…”

“…In total, 1400 tumours from 20 different types of cancers were analysed for LC3B, an autophagy marker, and it was found that increased expression was associated with metastasis and invasion [27] . Autophagy inhibition in rat sarcoma-mutant cancer cells was demonstrated to induce EMT by triggering NF-κB by p62/SQSTM1 [21] . Similarly, p62/SQSTM1 is important for stabilising Twist1, preventing its degradation [40] .…”

Bile acids increase intestinal markers via FXR/SNAI2/miR-1 axis in the stomach

“…SNAI2 (also known as Slug), a member of Snail superfamily, is one of the transcription factors of epithelial mesenchymal transition (EMT) [32]. In recent years, it has been found that SNAI2 is abnormally expressed in various kinds of malignant tumors and plays an important role in tumor progress and prognosis [33][34][35]. To investigate the role of SNAI2 in IM cells, we examined its expression level in IM tissues and BA-induced IM cells.…”

Autophagy and Its Relationship to Epithelial to Mesenchymal Transition: When Autophagy Inhibition for Cancer Therapy Turns Counterproductive

“…xenografts [46] HCC cell lines and xenografts [47] Loss of ULK1 to suppress autophagy in the MDA-MB-231 breast cancer cell line during hypoxia [48] Starvation- [49,50], TGF-β2- [51], or DRAM1induced [52] autophagy in hepatic carcinoma cell lines RAS-mutated cancer cells [53] TGFβ1-or rapamycin-induced autophagy in non-small cell lung cancer cells [54] Glioblastoma cell lines [55] Rapamycin-induced autophagy in CRC cell lines [56] Ovarian cancer cell lines [57] Cisplatin-induced autophagy in nasopharyngeal carcinoma cells [ MMTV-PyMT mice with FIP200 −/− conditional KO in mammary epithelial cells [40] Immunoediting…”