SCF E3 ubiquitin ligase can be inactivated by targeting its oncogenic components, including RBX1/RBX2, Cul-4A, or Skp2 via siRNA silencing approach or by pharmaceutical inhibition of cullin neddylation with a NAE inhibitor, MLN4924. Inactivation of SCF E3 ligase causes the accumulation of its substrates which suppress cancer cell growth by triggering multiple cancer cell killing pathways, including apoptosis, senescence and autophagy with the mechanisms subjected to future investigation.