Loss of lysosome-associated membrane protein 3 (LAMP3) enhances cellular vulnerability against proteasomal inhibition

Abstract

The family of lysosome-associated membrane proteins (LAMP) includes the ubiquitously expressed LAMP1 and LAMP2, which account for half of the proteins in the lysosomal membrane. Another member of the LAMP family is LAMP3, which is expressed only in certain cell types and differentiation stages. LAMP3 expression is linked with poor prognosis of certain cancers, and the locus where it is encoded was identified as a risk factor for Parkinson's disease (PD). Here, we investigated the role of LAMP3 in the two main cellular degradation pathways, the proteasome and autophagy. LAMP3 mRNA was not detected in mouse models of PD or in the brain of human patients. However, it was strongly induced upon proteasomal inhibition in the neuroblastoma cell line SH-SY5Y. Induction of LAMP3 mRNA following proteasomal inhibition was dependent on UPR transcription factor ATF4 signaling and induced autophagic flux. Prevention of LAMP3 induction enhanced apoptotic cell death. In summary, these data demonstrate that LAMP3 regulation as part of the UPR contributes to protein degradation and cell survival during proteasomal dysfunction. This link between autophagy and the proteasome may be of special importance for the treatment of tumor cells with proteasomal inhibitors.

The Transcriptional Activity of LAMP3 Gene Involved in Autophagocytosis in Colorectal Cancer LAMP3 Expression in Colorectal Cancer

“…The resistance induced by LAMP3 is primarily directed towards proteasome inhibitors used during chemotherapy. In conclusion, it has been found that increased expression of LAMP3 contributes to the development of autophagy and cell survival [6] [27]. It is important when developing new therapies, including molecularly targeted therapies, to inhibit the specific cytokine activating the signaling pathway involved in a particular disease.…”

“…This finding indicates that inhibition of autophagy may be an effective treatment for advanced stage cancer [21]. Autophagocytosis can be induced, among other things, by UPR-dependent signaling pathway activated by hypoxia or nutrient deficiency [6] [9]. The precise mechanism of action of this pathway is not yet known, and the genes involved in this process have not yet been identified [11].…”

“…As demonstrated by previous studies, autophagy has a crucial role in tumor development and metastasis, mainly to lymph nodes. It is believed that LAMP3 protein is involved in cancer cell resistance to therapy (chemotherapy and radiotherapy) and the mechanism of resistance involves the induction of the UPR pathway and autophagy [6]. Increased expression of ATF4 is associated with decreased sensitivity to certain types of therapy [22].…”

“…It is noted that there is a strong correlation between LAMP3 expression and tumor metastases. High level of LAMP3 mRNA significantly correlates with poor prognosis in patients with stage I and II tumors [4] [5] [6]. Furthermore, LAMP3 takes part in the invasion and migration of cancer cells as well as the induction of autophagocytosis [7].…”

“…In addition, it has been shown that less oxygenated tumors have a worse prognosis and higher incidence of metastasis compared with more oxygenated tumors [1] [7]. LAMP3 is involved in unfolded protein response (UPR) signaling pathway induced by hypoxia or stress factors [6]. One branch of the UPR pathway involving protein kinase RNA-like endoplasmic reticulum kinase/activating transcription factor 4 (PERK/ATF4) allows cells to survive by regulating angiogenesis, apoptosis and autophagy.…”