Controlling cell cycle, process by which cells progress and divide, is at the heart of cancer research therapies. Tumor cells signature often lays in high proliferation rate, alterations of multiple intracellular signaling networks and hijacking of programmed-cell death pathways. Implication of autophagy and lysosomal biology in cancer is still controversial. Lysosomes are catabolic vesicles involved in the degradation of biological material and need to be tightly regulated. Lysosomes may influence cancer formation and progression by regulating many complex processes of cell biology, such as cell signaling, cell death, nutrient sensing and cell metabolism. Lysosome function depends on lysosome acidification capacity modulated by proton pump v-ATPase activity and on its intracellular localization driven by motor proteins, mainly by motor protein kinesin KIF5B. We recently discover an innovative mechanism involving lysosomes impairment to induce mitotic error that could potentially lead tumor cells to cell death.