Tumoral acidosis promotes adipose tissue depletion by fostering adipocyte lipolysis

Adaptation to acidosis has been reported to induce a shift towards fatty acid metabolism. We observed that conditioned medium of HCT, FaDu and SiHa adapted to acidosis (pH6.5) induced higher lipolysis of primary subcutaneous and mesenteric adipocytes compared to cancer cells maintained at pH7.4. In order to identify the prolipolytic factors induced by acidosis, we examined the differences between cancer cells adapted to pH6.5 and those maintained at pH7.4 by RNA sequencing. Cancer cells adapted to pH6.5 showed profound alterations in their gene expression compared with cancer cells maintained at pH7.4. Here, we focused on predicted secreted genes. We determined that 84 altered genes predicted to be secreted proteins overlapped between the 3 cancer cell lines, 24 of which were overexpressed. The role of these overexpressed genes was determined in vitro. We studied their role in inducing adipocyte lipolysis and in the depletion of adipose tissue observed in cancer cachexia. Human colon HCT116, hypopharyngeal FaDu and cervix SiHa cancer cell lines were exposed to medium with pH adjusted to 7.4 or 6.5. pH6.5-exposed cancer cells were maintained at pH6.5 for a minimum of 1 month before.