Lactotransferrin Downregulation Serves as a Potential Predictor for the Therapeutic Effectiveness of mTOR Inhibitors in the Metastatic Clear Cell Renal Cell Carcinoma without PTEN Mutation

Abstract

Approximately 30% of clear cell renal cell carcinoma (ccRCC) patients develop metastatic spread at the first diagnosis. Therefore, identifying a useful biomarker to predict ccRCC metastasis or therapeutic effectiveness in ccRCC patients is urgently needed. Previously, we demonstrated that lactotransferrin (LTF) downregulation enhanced the metastatic potential of ccRCC. Here, we show that LTF expression conversely associates with the mTORC1 activity as simulated by gene set enrichment analysis (GSEA). Moreover, Western blot analyses revealed that the LTF knockdown promoted, but the inclusion of recombinant human LTF protein suppressed, the phosphorylation of Akt/mTOR proteins in the detected ccRCC cells. Kaplan–Meier analyses demonstrated that the signature of combining an upregulated mTORC1 activity with a downregulated LTF expression referred to a worse overall and progression-free survival probabilities and associated with distant cancer metastasis in TCGA ccRCC patients. Furthermore, we found that the LTF-suppressed Akt/mTOR activation triggered an increased formation of autophagy in the highly metastatic ccRCC cells. The addition of autophagy inhibitor 3-methyadenine restored the LTF-suppressed cellular migration ability of highly metastatic ccRCC cells. Receiver operating characteristic (ROC) analyses showed that the expression of the LTF and MTORC1 gene set, not the autophagy gene set, could be the useful biomarkers to predict 5-year overall survival rate and cancer progression in ccRCC patients. Significantly, the signature of combining mTORC1 upregulation and LTF downregulation was shown as an independent prognostic factor in a multivariate analysis under the progression-free survival condition using the TCGA ccRCC database. Finally, the treatment with mTOR inhibitor rapamycin predominantly reduced the formation of autophagy and ultimately mitigated the cellular migration ability of ccRCC cells with LTF knockdown. Our findings suggest that LTF downregulation is a biomarker for guiding the use of mTOR inhibitors to combat metastatic ccRCC in the clinic.

Lactoferrin mediates epithelial-mesenchymal transformation by regulating the PI3K/AKT/mTOR pathway to inhibit nasopharyngeal carcinoma metastasis

“…Local recurrence and distant metastasis remained major obstacles to the clinical treatment of NPC. EMT has become a key process of cell invasion and metastasis in most epithelial tumors (including NPC) [24,25]. Recent studies have shown that a large number of genetic or epigenomic changes and genetic instability jointly control NPC occurrence, which is a complex process involving the interaction regulation of numerous molecular networks [26,27].…”

“…The PI3K/Akt/mTOR pathway is one of the main downstream signal transduction pathways of LTF, and LTF exerts anticancer effects in various cancers by influencing the PI3K/Akt/mTOR pathway [24,25]. Thus, it is reasonable to speculate that the change in NPC cell phenotype caused by LTF may be due to the regulation of the PI3K/AKT/mTOR pathway.…”

Renal Cell Cancer – Insights in Drug Resistance Mechanisms

“…Notably, studies have revealed that the down-regulation of lactotransferrin, a significant protein in the innate immune system, promotes metastasis in ccRCC. Interestingly, this down-regulation also renders the ccRCC tumor cells more responsive to mTOR inhibitors, suggesting its potential as a predictor for therapeutic effectiveness (22).…”

LTF Induces Radioresistance by Promoting Autophagy and Forms an AMPK/SP2/NEAT1/miR-214-5p Feedback Loop in Lung Squamous Cell Carcinoma

“…It has been suggested in some reports that the LTF can regulate cell growth, migration, and invasion in several cancers 13 . For example, previous studies have found that LTF is associated with proliferation, migration, invasion and promoted apoptosis of clear cell renal cell carcinoma 14 , 15 . LTF has also been suggested to downregulate the development of nasopharyngeal carcinoma by inhibiting the proliferation through induction of cell cycle arrest and modulation of the MAPK signaling pathway 16 .…”