Abstract

The
lysyl oxidase (LOX) family consists of LOX and LOX like enzymes (LOXL). LOX and
LOXL2 have varying degrees of similarity in their structures and functions.
They catalyse the crosslinking of the extra cellular matrix (ECM) proteins and
promotes tumour progression and metastasis. The critical roles of LOX and LOXL2
in cancer development potentiate them as therapeutic targets.

In
this study, novel compounds targeting LOX and LOXL2 were investigated for their
effects on the proliferation, adhesion, migration and survival of clear cell
renal cell carcinoma (ccRCC) Caki-2 cells in
vitro. The expressions of genes involved in regulating cell proliferation,
migration, adhesion and apoptosis signalling pathways were studied as
well.                                           

The
results show that compound-1, 4 and 5 significantly inhibited Caki-2 cell
growth (p<0.01) following 72 hours treatment compared to negative control
(p<0.05).The cell
cycle analyses demonstrated that the three compounds increased proportion of
Caki-2 cells in the G1-phase (P<0.05), while proportion of cells in S- and
G2/M-phase decreased. Compound-1 and 4 significantly reduced the adhesion of
Caki-2 cells to ECM in vitro in
comparison to the negative control (P<0.05). Compound-4 and 5 significantly
inhibited Caki-2 cell migration following 24 hours treatment. The expressions
of RRM2, CDKN1B, CXCL16 and CD98HC were significantly downregulated
in compound-1, 4 and 5 treated cells in comparison to the negative control. The
expressions of MMP9 and CXCL12 were downregulated in compound-4
and 5 treated cells, but upregulated in compound-1 treated cells.

In
conclusion, all the three compounds displayed various degrees of anti-proliferation,
anti-migration, inhibition of cell-ECM adhesion, and induction of apoptosis
effects. These effects might be mediated by inhibiting LOX/LOXL2 expression, which lead to the changes of expressions of
downstream cell signalling genes such as RRM2,
CXCL16 and CD98HC. The anti-ccRCC effects of compound-4 were stronger than
compound-1 and 5 in vitro. Compound-4
might hold greater therapeutic promise for ccRCC treatment in the future.