Figure 4. Complex interplay between CMA and cancer biology.

Both reduced and increased CMA activity can be pro-oncogenic depending on the cellular context. Reduced CMA has been shown to increase DNA damage and reduce proteostasis providing thus an environment favorable for malignant transformation. However, once cells have undergone transformation, they upregulate CMA and utilize it to their advantage to sustain the Warburg effect and increase their resistance to cytotoxic stressors. The high dependence of many cancer cells on CMA to regulate their energetic balance highlights the possible therapeutic value of modulation of CMA in cancer. Blockage of CMA in cancer cells reduces tumor growth and metastasis by abrogating part of the Warburg effect and increasing the tumor susceptibility to cytotoxic agents. Abnormally high CMA has been proposed to contribute to the energetic crisis induced in certain cancers by blockage of other autophagic pathways.