Lactate Dehydrogenase B Controls Lysosome Activity and Autophagy in Cancer

Abstract

Metabolic adaptability is essential for tumor progression and includes cooperation between cancer cells with different metabolic phenotypes. Optimal glucose supply to glycolytic cancer cells occurs when oxidative cancer cells use lactate preferentially to glucose. However, using lactate instead of glucose mimics glucose deprivation, and glucose starvation induces autophagy. We report that lactate sustains autophagy in cancer. In cancer cells preferentially to normal cells, lactate dehydrogenase B (LDHB), catalyzing the conversion of lactate and NAD(+) to pyruvate, NADH and H(+), controls lysosomal acidification, vesicle maturation, and intracellular proteolysis. LDHB activity is necessary for basal autophagy and cancer cell proliferation not only in oxidative cancer cells but also in glycolytic cancer cells.

Cancer metabolism in space and time: Beyond the Warburg effect

“…Hence, the ox ida tive me tab o lism of lac tate pro motes au tophagy, which for ox ida tive can cer cells on fast for ward meta bolic mode rep re sents an an tiox i dant de fense sys tem that ac tively re cy cles dam aged/ ox i dized pro teins and or ganelles. Of note, lac tate also pro motes au tophagy in gly colytic can cer cells, where en doge nously pro duced lac tate can be re ox i dized to pyru vate and NAD re duced to NADH and H , thus pro vid ing pro tons to lyso somes [76]. This path way would op ti mize pro tein and or ganelle re cy cling for bioen er getic pur poses, and en sure pH home osta sis of the cy tosol.…”

“…The ox ida tive path way of lac tate is more con cise and, com par a tively to gly col y sis, does not ne ces si tate ATP in vest ment. But what could be the pri mary ad van tage for ox ida tive can cer cells to use lac tate is that pro tons de rived from the LDHB re ac tion in the cy tosol fuel lyso somes, ow ing to a di rect in ter ac tion be tween LDHB and V AT Pase at the sur face of these vesi cles [76]. Hence, the ox ida tive me tab o lism of lac tate pro motes au tophagy, which for ox ida tive can cer cells on fast for ward meta bolic mode rep re sents an an tiox i dant de fense sys tem that ac tively re cy cles dam aged/ ox i dized pro teins and or ganelles.…”

“…The re mark able de pen dency for sur vival of hy poxic/ gly colytic can cer cells on the meta bolic pref er ences of nor moxic/ ox ida tive ones mo ti vated the de vel op ment of strate gies aimed to in ter fere with the ex change of lac tate. Ther a peu tic in ter ven tions could be aimed at in hibit ing MCT4 in hy poxic can cer cell com part ments [86], in hibit ing MCT1 [5,[87][88][89] and lac tate up take [90,91] in oxy genated/ ox ida tive can cer cells, in hibit ing LDHB [76,92] or, pos si bly, in hibit ing the mi to chon dr ial pyru vate car rier in ox ida tive can cer cells [93]. In our opin ion, fu ture ther a peu tic de vel op ments should aim at tar get ing the ox ida tive path way of lac tate in can cer cells that re side close to drug de liv er ing blood ves sels.…”

Can glyphosate’s disruption of the gut microbiome and induction of sulfate deficiency explain the epidemic in gout and associated diseases in the industrialized world?

“…Thus, exposure to PPAR-γ ligands following the inflammatory response may be the mechanism by which the inflammation is resolved. 6 It is intriguing that lactate (pK a 3.86) supports lysosomal acidification and autophagy in tumour cells [172].…”

Dual Roles of CD38 in Autophagy

“…Actually, the basal autophagy activity is essential for cell homeostasis, involving cell growth, survival, development and death. The levels of autophagy must be precisely regulated, as indicated by the fact that dysfunctional autophagy has been related to wide ranges of human diseases, such as cancer [24] [25], neurodegenerative diseases [26], myopathies [27], gastrointestinal disorders [28], heart and liver diseases [29]. The most interesting is the study about autophagy and cancer.…”