A positive feedback loop between GRP78 and VPS34 is critical for GRP78-mediated autophagy in cancer cells.

Autophagy and GRP78 overexpression are two important means by which tumor cells resist microenvironmental stress and chemotherapeutic drugs; however, the relationship between autophagy and GRP78 remains unclear. Here, we found that forced expression of GRP78 in tumor cells promoted autophagy, which was indicated by alterations in the levels of autophagy related proteins, such as increased VPS34 and LC3-II, and decreased p62 and LC3-I. Consistently, GRP78 knockdown suppressed tumor cell autophagy. Our results further demonstrated that GRP78-induced autophagy was mediated by VPS34, and that UPR-associated autophagy was also involved. GRP78-overexpressing cells treated with VPS34 siRNA reversed the autophagy induced by GRP78. Importantly, the expression of microRNA-143 (miR-143) was decreased in GRP78-overexpressing cells, and the increased expression of VPS34 was reversed by treatment with miR-143 mimic. This demonstrated that miR-143 plays a key role in GRP78's mediation of VPS34 expression. In addition, GRP78 acetylation was also involved in the occurrence of autophagy through upregulating VPS34. In turn, high expression of VPS34 promoted GRP78 transcription by modulating the GRP78 transcription factor ATF6. Moreover, VPS34 could enhance GRP78 protein stability by inhibiting GRP78 degradation via the ubiquitin-proteasome pathway. Collectively, the results revealed a positive feedback loop between GRP78 and VPS34 in tumor cells that might be important for autophagy during tumor development.